Scanning electron microscopy of the mammalian organ of Corti: assessment of preparative procedures.

Different fixation, drying and coating procedures have been applied in preparation of the organ of Corti for scanning electron microscopy (SEM), and structural features of the apical surface of the tissue in unfixed, freeze-fractured preparations used in assessing their effects on morphology. Fixation with glutaraldehyde alone or osmium tetroxide alone causes artefacts that are substantially avoided when tissue is doubly fixed in glutaraldehyde followed by osmium. Significant improvements in preservation are also obtained when tissue is additionally processed through thiocarbohydrazide-osmium (TOTO) processing. In addition to providing a conducting coat, it stabilises the tissue against deformations that might otherwise occur during drying, and reduces the extent of tissue shrinkage. Freeze-drying of TOTO processed tissue produces less tissue distortion than critical point drying (CPD) but is not so easy to apply routinely. The distortions of structure in TOTO-processed CPD tissue are not significant and this may be the preferred procedure for routine use, but air drying from hexamethyldisilazane is a useful alternative, producing results as good as those from CPD samples if TOTO processing is applied beforehand. One particular advantage of freeze-drying, though, is that after freezing, brittle fracture through the tissue can occur making examination of intracellular structure by SEM relatively easy. However, again, TOTO processing prior to freezing is of value as this appears to prevent the formation of large ice-crystal during freezing. Examination of isolated outer hair cells by SEM shows that isolation procedures do not cause significant damage to the stereociliary bundles.


Review and new case reports on scanning electron microscopy of pili annulati, Monilethrix and Trichothiodystrophy.

Pili annulati, Monilethrix and Trichothiodystrophy are uncommon conditions in which the hair shaft has a distinct appearance as seen by optical microscopy and scanning electron microscopy (SEM). We report several new cases and review the characteristic ultrastructural abnormalities investigated by SEM. Pili annulati: abnormal areas which show a longitudinal, "curtain-like" folding of the cuticular cells, alternating with normal areas. The latter present regularly non-systematized, superficial depressions. Hair specimens of the patient's mother show the same surface irregularities. Monilethrix: most hair shafts show variations in thickness giving a typical nodal appearance. In the isthmus area we noticed longitudinal ridging and cuticular scales that are extended lengthwise in a fish-scale-like pattern. In the nodus area a smooth surface due to a complete loss of cuticular cells, was observed. Trichothiodystrophy: the hair morphology observed by SEM is characterized by severe cuticular and secondary cortical degeneration along the entire length of the flattened hair shaft, with longitudinal ridging, cuticle loss, trichlorrhexis nodosa formation and trichoschisis. SEM observations show morphological abnormalities which are characteristic for each pathological condition described. This method may provide data that add some clarity in the surface changes of the different hair shaft anomalies.


Detection of X-ray damage repair by the immediate versus delayed plating technique is dependent on cell shape and cell concentration.

A method commonly used to measure the ability of cells to repair potentially lethal damage (PLD) is to compare immediate plating (IP) and delayed plating (DP) survival. Lower cell survival under IP conditions relative to that after DP conditions has been interpreted to indicate a higher ability of cells to repair potentially lethal damage (PLD) under DP conditions. However, this IP radiosensitization has not been observed in several cell lines and tumor models. IP conditions involve treatment of cells with trypsin and plating them into fresh growth medium. We have investigated the possibility that radiosensitization under IP conditions may be related to both the cell-shape and the nutrient concentration in growth medium (GM, MEM + 15% serum). This idea predicts that the IP and DP survival of spheroids will show a response similar to the IP survival of cells in monolayers and that the IP and DP survival of crowded monolayer cells in high densities will be the same. Chinese hamster V79 cells grown in monolayers (spread cells) and spheroids (clumps of round cells) were used. The IP survival was lower than the DP survival for spread log phase monolayer cells but not for round log phase cells in spheroids. Radiosensitization of cells by fresh (as opposed to spent) growth medium was absent for high density plateau phase cells in monolayers at or above 2 x 10(6) cells/ml. However, PLD repair could be demonstrated in spheroid cells and in high density plateau phase cultures by exposing cells to hyperthermia or hypertonic saline. Comparison of immediate plating versus delayed plating survival detects PLD repair only in well spread low density monolayer cells, but not in round spheroid cells nor in dense monolayer cells at > 10(7) cells/25 cm2 flask/5 ml medium. The absence of a difference between IP and DP cell survival does not mean that PLD repair is absent. Incorrect prediction of tumor response to radiotherapy can occur when PLD repair capacity is assayed as a ratio of DP/IP survival. More than one method must be used to measure the capacity of cells to repair their PLD.


Relationship between villous shape and mural structure in neutron irradiated small intestine.

Previous work on irradiation of mouse small intestine has assessed the changes produced by counting crypts/microcolonies, scoring villous shape or examining morphological changes in specific parts of the wall. This paper used scanning and transmission electron microscopy to study the effects of whole body irradiation with 5 Gy neutrons on the surface and internal features of the intestinal wall of CFLP mice, 1 day, 3 days and 7 days after treatment. Empirical scores from the ultrastructural findings were inserted into a Morphological Index display calculated from analytical data based on cell counts and area measurements obtained from resin histology sections. The final data display showed that the neutron irradiation produced marked structural changes in different cells and tissues by 1 day. These changes were maximal at 3 days with substantial improvement by 7 days. When this data display was compared with scores taken from scanning electron microscopy of the mucosal surface, the change in villous shape from erect fingerlike projections to lower profiles less suited to absorption was seen to correlate more with changes in the smooth muscle than with the epithelial cryptal compartment.


Mechanisms of ciliary movement: contributions from electron microscopy.

A brief review of important contributions of electron microscopy to the study of ciliary motility is presented. The electron microscope was used to show the universality of axonemal structure of cilia, and to develop the sliding microtubule model of ciliary motility and later the switch point hypothesis to explain the conversion of sliding into bending. Unexpectedly, insights into the importance of cilia in human health have stemmed from these studies.


[Acute severe asthma: emergency diagnostic and therapeutic measures].

There is growing evidence that the prevalence and the severity of bronchial asthma are rising in the industrialized countries despite a marked increase in the sale of antiasthmatic drugs. Non-diagnosis and undertreatment of patients with asthma may be causative factors. Identification of acute severe asthma by the physician and early hospitalization of patients at risk are important factors in lowering morbidity and mortality. Indicators of severe asthma on initial assessment are a history of poor long-term control (previous hospital admissions, regular use of inhaled beta agonists, maintenance oral corticosteroid treatment, prolonged current attack and low or greatly varying peak flow values) and clinical examination with spirometry as the most objective tool. A peak expiratory flow (PEF) of < 30% pred. (< 100-120 l/min) and a forced expiratory volume in the first second (FEV1) of < 25% pred. (< 0.7-1.01) indicate severe asthma. The physical signs and symptoms correlate well with the spirometric values but show too much variability to be used alone. A PaCO2 value of > or = 45 mm Hg (6 kPa) is very specific for severe asthma. Patients whose asthma is considered severe on initial assessment must be referred to a hospital. In the emergency ward the documented response to treatment, i.e. the speed of recovery, is the most important parameter for discharge or admission to hospital. Only patients who improve within a few hours, who remain clinically stable and who have a PEF > 75% pred. or an FEV1 > 50% pred. should be discharged.


[Swiss quality control in bacteriology and mycology 1989-1991].

Since 1983 there has been a voluntary quality assessment scheme (QAS) for bacteriology and mycology laboratories in Switzerland directed by the Committee for Quality Control of the Swiss Society for Microbiology. For the first time, the results of this QAS for the period between 1989 and 1991 are made available to a wider public. During the period in question, a steadily increasing number of participants received three samples containing microorganisms four times a year for identification and susceptibility testing. A mean percentage value of a point rating, with a maximum of 12 points, was calculated every year for each laboratory. Values of < or = 75% were defined as insufficient. For a first evaluation, laboratories were assigned to the categories of cantonal (and university) laboratories (C/U), private laboratories (P), and hospital laboratories (H, in hospitals which are neither university nor other tertiary care centres). Significant differences were detected between C/U and P on the one hand and H on the other. As a rule, H obtained poorer results than the two categories, examined fewer specimens, and their percentage with results < or = 75% was significantly higher. The second evaluation classified laboratories according to their recognition by the Swiss Federal Department of Public Health (FDPH). For statistical reasons, H had to be grouped with C/U. Nevertheless, their share of non-recognized laboratories was exceedingly high (15 out of 17 participants in 1991). Recognized laboratories constantly showed a better performance than non-recognized laboratories, examined more specimens, and their number of laboratories obtaining results < or = 75% was much lower.(ABSTRACT TRUNCATED AT 250 WORDS)


[New faces, forgotten diseases:border medical examination of asylum seekers' children 1990-1991].

Hitherto there has been no epidemiologic basis for the extent of initial medical examination (IME) of children of refugees. In Switzerland little data is published on the incidence of diseases among refugees; in particular information on their children is scarce. We report the results of IME in these children in the Canton of Zürich from 1 July 1990 to 30 June 1991. The Federal Refugees Office assigned 1487 children to the Canton of Zürich. 920 children (61.9%) were registered, 259 (17.4%) at Zürich Children's Hospital and 661 with local physicians (44.5%). The current IME included a tuberculin skin test only, with additional hepatitis B screening of children from high risk countries. At the Zürich Children's Hospital the IME was extended: every child was examined clinically and a history was taken. The findings in the children examined at the Zürich Children's Hospital were as follows: 171 (66%) were healthy. 5 children (2%) had tuberculosis, 2 (0.8%) vitamin D deficiency rickets, 5 (2%) had iron deficiency anemia, 9 had hepatitis B (all recovered), 25 (9.7%) had various skin diseases and in 51 a variety of diseases of differing clinical significance were diagnosed. The local physicians found a similar incidence of tuberculosis, vitamin D deficiency rickets, iron deficiency anemia and skin diseases.(ABSTRACT TRUNCATED AT 250 WORDS)


[Long-term course in differentiated thyroid gland carcinoma].

545 patients with differentiated thyroid carcinoma were followed up for periods ranging up to 25 years after first treatment (mean 8.1 years, 65% for over 5 years). 72% of patients with papillary carcinoma (n = 270), but only 52% with follicular carcinoma (n = 275) remained tumor-free during the further course. Residual malignancies persisted for more than the first year in 6% and 17% of patients respectively; there were tumor recurrences after an apparently tumor-free interval in 22% and 31% respectively, the latest after 12 and 27 years respectively. 6% and 19% of patients respectively died as a direct result of the tumor (and a group of equal size from other causes), half due to residual and half due to recurrent carcinoma. With regard to residual tumors, few significant risk factors were found preoperatively, comprising distant metastases (factor = 34 and 20 for papillary and follicular tumors respectively), age over 50 years (F = 6.4 and 5), infiltrating growth of primary tumor (F = 4 and 4.3), and regional lymph node involvement (F = 1.2 and 2). However, these factors were of little use in predicting the risk of the more frequently observed tumor recurrence, with maximum factors of 2 (for T4 and N+ stage) for papillary thyroid cancers and 1.5 for follicular cancers. At risk for recurrence were patients in whom total thyroidectomy was not performed (F = 2.3 and 2) and those who did not receive postoperative radioiodine treatment (F = 3), irrespective of age and tumor stage. Therefore, any individualizing regimen beginning with the first treatment has a bearing not only on residual tumor's 50% contribution to mortality. The equally large contribution of recurrences to tumor death can be influenced only by thyroidectomy or, more realistically, by strumectomy combined with early ablation of thyroid remnants with radioiodine. Postoperative radiotherapy of the neck region did not prevent tumor recurrence, and although hormonal suppression was never given the results compared well with the best of published long-term follow-up studies. There were no acute or late complications that could be ascribed to radioiodine treatment. However, a strict strategy of the reducing the administered doses was adopted: the ablation dose was half that used previously (1.5 GBq, i.e. 45 mCi on average), tumor treatment was halted even where residual uptake was observed scintigraphically (in 44% of patients treated) and radioiodine was no longer used for follow-up investigations.(ABSTRACT TRUNCATED AT 400 WORDS)


[Boutonneuse fever in Switzerland: apropos of a case report].

The history and clinical presentation of Mediterranean spotted fever in a 72-year-old male patient with polycythemia vera are described. The patient presented soon after arrival in Bordeaux (France) with fever, arthralgia and an erythematous maculopapular skin rash involving the palms and foot soles. The clinical course was complicated by pulmonary involvement resulting in dyspnea and hypoxemia. The patient denied tick bite but had contact with a dog. Antibiotic therapy with doxycycline resulted in rapid improvement of all clinical findings. A significant rise in antibody titer against Rickettsia conorii confirmed the diagnosis. The case is discussed in relation to other published cases in Switzerland and illustrates that this infection can be acquired outside an endemic area.


[Anatomo-clinical discordance: analysis of a series of consecutive autopsies].

In order to assess the level of agreement between clinical and autopsy diagnoses in the medical wards of a city and teaching hospital, we studied 94 consecutive patients autopsied during a 12 months' period. The rate of autopsy in this study was 59%. The main diagnosis was confirmed at autopsy in 80% of the cases, more precisely defined in 11% and discovered in 9%. Among 124 secondary diagnoses, 34% were diagnosed by the pathologist. The retrospective analysis of the cases in which there was disagreement between clinical and autopsy diagnosis showed that in 8 of them (8.5% of all patients), a clinical impact on survival was possible. However, all of these patients were over 80 and had multiple and/or terminal diseases. Thus, the real impact of these diagnostic errors is debatable.


[Hospitalization of tuberculosis patients in Swiss hospitals in 1990].

Despite a wide spectrum of efficient chemotherapies, tuberculosis patients even today are often given inpatient treatment. This fact is shown by the MSV, the Medical Statistics of VESKA (Association of Swiss Hospitals), which is coded according to the ICD key and numbers tuberculosis forms from 010 to 018. The MSV figures for the year 1990 in its associated clinics are: total diagnoses 685,204, principal diagnoses 346,671, number of nursing days 4,613,737 and average stay 13.3 days. At the same time, the following data were registered: total of 1009 hospitalizations with a tuberculosis diagnosis, including 555 patients with a principal diagnosis of tuberculosis. Hospitalizations due to tuberculosis as the principal diagnosis account for 13,995 nursing days, which corresponds to 0.3% of the total. The average hospital stay lasts 25.2 days. In both diagnosis groups, first place is occupied by pulmonary tuberculosis (011) with 67.0% and 70.5% respectively, and among the extrathoracic forms 013-018, urogenital tuberculosis (016) with 6.3% principal diagnosis. The cases with the principal diagnosis of tuberculosis generate (partly calculated, partly estimated) hospital costs of approximately Sfr. 4.9 million and a paid wage total of some Sfr. 1.5 million. In the case of secondary tuberculoses of the 2nd and 3rd position in the statistics, analogous sums of an estimated total of Sfr. 2.4 million are added. It is therefore safe to say that tuberculosis is still not without financial significance in Switzerland.(ABSTRACT TRUNCATED AT 250 WORDS)


[Controversial aspects of stage I skin melanomas].

Melanoma is still the most frequent cause of death for diseases arising in the skin. The mortality rate is approximately 25%, tumor thickness, sex and localization being the most important prognostic factors. It is still unclear whether the margin of excision, type of anaesthesia and the pattern of follow-up should be taken into consideration in relation to the individual prognostic groups.


[Moderate Paget's disease treated with pamidronate (APD): experience in 43 patients with a single 60 mg infusion of varying duration of 1-to-24 hours].

Pamidronate disodium (APD) given as a single 60 mg intravenous infusion over 24 hours was shown to be an effective treatment for Paget's disease of bone. To further improve the feasibility of a simple treatment that ensures compliance in elderly outpatients (pts), we investigated the effectiveness of a single 60 mg APD intravenous infusion given over 8 hours (12 pts), 4 hours (9 pts) and 1 hour (10 pts) compared with that over 24 hours (12 pts). Infusion rate of APD was 7.5, 15 and 60 mg/h respectively, in comparison with 2.5 mg/h previously. Clinical improvement and biochemical remission were observed in all patients. Side effects, limited to mild transient fever and local transient increase in bone pain, occurred in 9 patients (2-3 pts in each group). There was no difference in the fall of plasma alkaline phosphatase and of urinary hydroxyproline between the 4 infusion rates. Plasma alkaline phosphatase (U/l, mean +/- SEM) decreased from 263 +/- 34 to 110 +/- 8 (1 h infusion), from 251 +/- 26 to 102 +/- 9 (4 h), from 237 +/- 23 to 95 +/- 9 (8 h) and from 256 +/- 29 to 97 +/- 7 (24 h), from day 0 to day 180 respectively (all p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


[Diagnosis of hydroxyapatite disease].

The possibility of detecting hydroxyapatite crystals in synovia in a routine setting has been studied prospectively. Coloration of the crystals with alizarin red-S was the method of choice. The diagnostic results were markedly improved by simultaneous observation of a freshly prepared positive control synovia.


[The biotransformation of NSAIDs: a common elimination site and drug interactions].

Many NSAIDs are eliminated predominantly through hepatic biotransformation in man. We have studied, in human hepatic microsomes, the role of specific cytochrome P450 isozymes in the formation of the major metabolites of oxicam (piroxicam and tenoxicam), phenylacetic (diclofenac) and propionic acid (ibuprofen) derivatives. A common isozyme (P450TB, CYP2C subfamily) controls the major elimination pathway of these NSAIDs. We have also determined, in two in vitro models of P450TB, the affinity for this isozyme of NSAIDs from other chemical classes (acetylsalicylic acid, mefenamic acid and indomethacin). All NSAIDs tested displayed a high affinity (3-300 microM) for cytochrome P450TB. Cytochrome P450TB plays a major role in the elimination of several NSAIDs with different chemical structures. NSAIDs are substrates as well as potential inhibitors of cytochrome P450TB. Their elimination can therefore be reduced by concomitant administration of known inhibitors of P450TB (antifungals, antibacterial sulfonamides, calcium channel blockers).


[Preliminary experience with the Storz Modulith SL 20 lithotriptor in reno-ureteral lithiasis].

The authors report their initial results in ESWL of urinary calculi with the Storz Modulith SL 20 lithotriptor, a multipurpose device for both urinary and biliary stone treatment. During 176 sessions, a total of 144 cases (81 renal and 63 ureteral) were treated and then, followed up. The over-all rate free of stones was 86.8% (90.1% for kidney and for ureteral stones). The treatment rate was 1.23 per patient. Auxiliary procedures before ESWL were performed in 7.9% of the sessions: insertion of "double-J" stent or nephrostomy tube; all ureteral stones received "in situ" treatment. Mean number of shock waves per session was 1836.1 (range 300-3020). The maximum voltage on the average reached was 17.1 kv. Sedo-analgesia by Diazepam and Ketoprofen was given in 75% of the cases. No serious complications were observed. The experience with this machine is discussed in regard to performance; the advantages of its fluoroscopy and ultrasound guided system of focusing are stressed.


Deep dorsal vein arterialization in vasculogenic impotence: our experience.

We describe our experience of surgical therapy for vasculogenic impotence, using a technique of arterialization of the deep dorsal vein. This technique was chosen because vascular anastomosis can easily be performed, and because of the possibility of inducing haemodynamic mechanisms which favour the maintenance of rigidity, using venous arterialization. The operation was performed on 22 selected subjects with positive results. 12 patients (55%) reported erections which enabled them to have satisfactory sexual relations one year after follow-up. From the data reported we can conclude that penile revascularization, using the technique of arterialization of the deep dorsal vein, in well selected cases of vasculogenic impotence, should be considered a valid alternative to a penile prosthesis implant.


[Chronobiological approach to renal colic].

The concentration of lithogenic and antilithogenic substances in urine shows circadian fluctuations. With this investigation we intended to verify the presence of a chronobiologic rhythm of colic pain in urinary tract calculosis. Four hundred and forty seven consecutive patients with a clinical symptomatology related to urinary tract colic pain were studied. They were subdivided according to sex and age (297 M, 150 F; > or = 65 ys 29, < 65 ys 428). Urinary and blood chemical analysis and instrumental examinations permitted to confirm the clinical diagnosis. To evaluate the circadian and circannual variability, acute events were grouped into one calendar year by the month and into a ideal day by the hour of occurrence respectively. Chronobiologic analysis was performed utilising Halberg single cosinor test. The results pointed out that the symptomatology related to urinary tract colic pain presents a circadian rhythmicity either in patients as a whole or in single subgroups (males, females, younger or older than 65 ys). Besides no seasonal variability was demonstrated, perhaps because of the mild climate present in the geographic area in which the study was carried on.


[Nutritional status and chronic renal insufficiency].

The occurrence of malnutrition in patients with chronic renal failure has been well documented, mostly in patients undergoing regular dialysis: these patients often suffer from protein-calorie malnutrition, but more seldom there are disturbances to be due to deficit of 1,25 dihydroxyvitamin D3, folic acid, vitamin B6, iron, zinc and L-carnitine, mostly in patients who do not get adequate supplementation. There are several causes for protein-calorie malnutrition in chronic renal insufficiency. These include uremia per se, altered hormonal milieu, abnormal amino acid metabolism due to uremia or to loss of metabolically active renal tissue. Dialysis treatment improves some of these abnormalities, but introduces others. On the other hand, it is well established that morbidity and mortality in chronic renal failure are influenced by their nutritional status: therefore it is important to know the factors and the mechanisms that cause malnutrition for its prevention, recognition and correction.


Chronic interstitial cystitis. Successful treatment with intravesical idocaine.

A case of interstitial cystitis in a patient with a 5-year history treated by intravesical instillations of Lidocaine is reported. The repeated treatment relieved the patient from her pain and induced a potent anti-inflammatory effect on the bladder wall. The concentrations of plasma Lidocaine were between 1.4 and 1.1 mg/ml. No adverse reactions were reported with a follow-up of 2-years.


Angiosarcoma of the adrenal gland. Case report.

The vascular tumours of the adrenal gland are rare, both the benign and the malignant ones. Twenty two cases from the literature are reviewed in a paper by Kareti et al., 1988, among which only one own case of angiosarcoma the authors deem to be the first to be reported. A second case of angiosarcoma of the left adrenal gland, in a 67 y. old man, is herein reported. Notwithstanding a through surgical removal, a quick fatal progression of the disease ensued. Perhaps, considering the high malignancy of these rare tumours, an adjuvant form of treatment seems to be advisable.


[Oncocytic carcinoma in a horseshoe kidney].

The Authors report a rare case of oncocytoma in a horseshoe kidney. The diagnostic path needed to assess the precise anatomy of the malformation and tumoral staging is out lined. Oncological problems dealing with oncocytoma are further discussed, together with the technical and surgical issues pertinent to the clinical case.


Urethral manipulation syndrome (Kelâmy syndrome): acquired ventral penile deviation.

Fibrosis of the corpus spongiosum penis, caused by urethral manipulation and the resulting ventral penile deviations are known as the urethral manipulation syndrome (Kelâmi Syndrome). This condition is due to fibrosis and scarring of the corpus spongiosum penis after any kind of urethral manipulation. We have observed 4 urethral manipulation syndromes developing after urethrocystoscopy and presented them.


[Early diagnosis and proper treatment of infections of the male genital system].

The appropriate methods for early detection and the more effective drugs for best treatment of "other" Sexually Transmitted Diseases (STD) are reviewed: the most important target is to prevent sequelae of infection like seminal phlogosis, woman's pelvic phlogosis, impotency, sterility.


[Intrinsic endometriosis of the ureter. Clinical case].

Endometriosis is defined as the presence of endometrial tissue outside the cavity of the uterus. The urinary tract is rarely affected, only 1 to 11%. Bladder is the most frequent urinary localization while the ureteral involvement is rare. We report a case of intrinsic ureteral endometriosis in a woman with left hydronephrosis, lumbar pain and septic fever. Instrumental and laboratory investigations can hardly lead to a reliable diagnosis of ureteral endometriosis. A final diagnosis is feasible only by histologic examination, which obviously implies surgery.


Drug discovery and development in the pharmaceutical industry.

The discovery and development of new anticancer drugs is a complex and largely empirical process. New compounds can be discovered by screening, modification of existing compounds, rational drug design, and serendipitous basic research observations. Selection of compounds for clinical trials depends on assays of uncertain predictive value. In the pharmaceutical industry, priorities for development of potentially active entities are set and available resources allocated based on the availability and cost of supplies, patent status, potential spectrum of activity, ability to meet regulatory requirements, and market assessments. Competition for resources also occurs from noncancer drugs, eg, cardiovascular agents. Clinical development (testing and approval for commercial distribution) requires close attention to the requirements of national regulatory agencies such as the United States Food and Drug Administration. The arbitrary nature by which compounds with antitumor potential are chosen for development means that some that would be useful never reach clinical trial and others are never made generally available. This article reviews the decision making process in the pharmaceutical industry by which compounds are identified and selected for clinical trial, the regulations in the United States that govern such trials, and what is required to have the drug approved for commercial distribution.


The National Cancer Institute: cancer drug discovery and development program.

The discovery and development of novel therapeutic products for the treatment of malignancy is vitally important to those physicians responsible for the management of cancer patients. A description of the ongoing efforts at the National Cancer Institute (NCI) is intended to provide insight into those complex processes necessary to accomplish this mission. An update on the NCI's revised cancer screen is accompanied by a brief summary of those new agents scheduled to be entered into clinical investigation in the near future. The tremendous potential advantages and challenges associated with the use of a molecular approach to cancer drug design are discussed. Despite the differences of opinion that may exist regarding the optimal strategies for accomplishing the mission, there is no disagreement regarding the importance of the effort to find effective new therapies for cancer patients.


New vinca alkaloids and related compounds.

The vinca alkaloids remain among the most useful classes of anticancer agents used in the clinic today. However, previous analogs of these agents have not realized either increased safety or an enhanced antitumor spectrum. Currently, three derivatives are in clinical trial: vinorelbine, vintripol, and vinxaltine. Vinorelbine has shown consistent antitumor activity in patients with breast carcinoma and is in phase III trials in the United States, Europe, and Japan. Vintripol and vinxaltine, vinca alkaloids conjugated to amino acids, are in early clinical trials in Europe. The dose-limiting toxicity of these agents is leukopenia. A similar agent with a different chemical structure, rhizoxin, is in early phase II clinical trials with initial activity noted in breast carcinoma. The ultimate role of these agents in treatment of human malignancy awaits the results of ongoing studies.


The anthracyclines: will we ever find a better doxorubicin?

The anthracyclines are the class of antitumor drugs with the widest spectrum of activity in human cancers, and only a few cancers (eg, colon cancer) are unresponsive to them. The first two anthracyclines were developed in the 1960s. Doxorubicin (DOX) differs from daunorubicin (DNR) only by a single hydroxyl group. This fact has spurred researchers worldwide to find analogs of DOX that have less acute toxicity, cause less cardiomyopathy, can be administered orally, and/or have different, or greater, antitumor efficacy. Five DOX/DNR analogs are marketed in other countries, and one (idarubicin) is available in the United States. None of these analogs have stronger antitumor efficacy than the original two anthracyclines, but there are some differences in toxicity. Methods have been fashioned to keep the peak plasma level of DOX muted to minimize cardiotoxicity, but the only apparently effective method available so far (prolonged drug infusion) is cumbersome. The bisoxopiperazine class of drugs (especially dexrazoxane) provides protection against anthracycline-induced cardiomyopathy and has much promise for helping mitigate this major obstacle to prolonged use of the anthracyclines. The DOX analogs being evaluated in the 1990s have been selected for their ability to overcome multidrug resistance in cancer cells. Thirty years after discovery of the anticancer activity of the first anthracycline, some means of reducing anthracycline toxicity have been devised. Current studies are evaluating increased doses of epirubicin to improve anthracycline cytotoxicity, while limiting cardiotoxicity, but at present DOX still reigns in this drug class as the one having the most proven cancerocidal effect.


The anthrapyrazoles: a new class of compounds with clinical activity in breast cancer.

The anthrapyrazoles are DNA-binding anticancer agents with broad spectrum preclinical activity and reduced potential for free radical generation compared with doxorubicin. In early clinical trials, the dose-limiting toxicity has been leukopenia, other side effects being minor, and promising antitumor activity has been shown, especially in breast cancer. It remains to be confirmed that the anthrapyrazoles are less cardiotoxic than doxorubicin, but it is clear that these drugs are showing real promise, appear significantly less toxic than doxorubicin, and seem to represent a genuine therapeutic advance.


Antifolates: the next generation.

A number of promising new antifolates have been entered in clinical trials in recent years. These agents have been rationally designed based on the current understanding of folate transport and metabolism and of the mechanisms by which cells become resistant to methotrexate. Methotrexate-resistant cell lines are generally sensitive to one or more of the newer antifolates, which differ from methotrexate by being either more lipid soluble, more extensively polyglutamated, or by inhibiting folate-requiring enzymes other than dihydrofolate reductase. Five of the agents furthest along in clinical testing, trimetrexate, piritrexim, edatrexate, lometrexol, and D1694, are discussed. These drugs offer exciting opportunities to expand the role of antifolates in cancer chemotherapy, as well as in antimicrobial and antirheumatic therapy.


The current status of new platinum analogs.

Nine platinum analogs are currently in clinical development, including three that contain the diaminocyclohexane substituent and five that contain the cyclobutanedicarboxylato leaving group. Many of them have shown activity in at least one cisplatin (CDDP)-resistant cell line, most commonly L1210 murine leukemia. In addition, most were less nephrotoxic than CDDP in preclinical evaluations. While these agents share certain key structural similarities, there are important differences in their toxicity profiles that may be exploitable in future combination therapies. Though neuropathy has been a troubling toxicity with two of the three diaminocyclohexane (DACH) compounds, it differs in that it appears to be less chronic and cumulative with oxaliplatin (I-OHP), which is also associated with much less myelosuppression. Of the cyclobutanedicarboxylato compounds that are structurally related to carboplatin (CBDCA), there are several notable differences. For several compounds, isolated neutropenia has been dose-limiting and thrombocytopenia, which is common with CBDCA, has been uncommon. Like CBDCA, neurotoxicity has not been an issue with this group. Therefore, the potential for dose escalation with a colony stimulating factor (CSF) appears enhanced. Furthermore, promising early clinical leads, such as the substantial response rates in cervix and head and neck cancers with 254-S and in patients with colon cancer using circadian modulation of I-OHP, require careful evaluation. Preclinical synergy data are also cited that suggest other potential clinical leads. The development of a number of these agents has been complicated by unanticipated issues, including unexpected chronic dose-limiting neurotoxicity with ormaplatin (OP), formulation and stability problems with liposomal-neodecanoato-diaminocyclohexane platinum (II) (L-NDDP), and problematic nephrotoxicity with zeniplatin (ZP). However, several of these new compounds are likely to enter broader phase II and III development and should provide important information not only about the utility of the agents themselves but also about the predictive value of some of these preclinical models of CDDP resistance.


Trans-retinoic acid and related differentiation agents.

Interest in retinoids as therapeutic agents has developed as a result of the observations of remission induction with all-trans retinoic acid (tRA) in patients with acute promyelocytic leukemia (APL), and of high objective response rates noted with the combination of cis-retinoic acid (cRA) with interferon-alpha in squamous cell carcinomas of skin and cervix. The therapeutic experience with RA in APL is discussed in this article from the perspectives of new information concerning retinoid biology, observations related to the development of the retinoid syndrome, complex pharmacology of this agent, and possible explanations for development of retinoid resistance. The current National Cancer Institute-supported drug development strategy for RA used alone or in combination with other differentiating agents, and the potential therapeutic uses in cancer for other retinoids are also discussed.


Developing partnerships for health and social science research: the International Clinical Epidemiology Network (INCLEN) social science component.

A decade after its inception, the International Clinical Epidemiology Network (INCLEN) adopted a social science component. Health social science concepts were added to a physician training curriculum encompassing epidemiology, biostatistics and clinical economics, and a position was created for qualified social scientists at 26 clinical epidemiology units in developing country medical schools. This paper describes the INCLEN model for strengthening partnerships among clinical epidemiologists and social scientists. The rationale for interdisciplinary training is presented along with the difficulties inherent in attracting social scientists to a new career path. These include problems of recruitment, training curricula, re-entry, and career sustainability. The need is identified for collaborative international efforts to promote an infrastructure for professional growth and sustainable careers in health social science.


A strategy for promoting improved pharmaceutical use: the International Network for Rational Use of Drugs.

Over the last decade, pharmaceutical selection, procurement, distribution, and financing have improved as a result of essential drugs programs. However, despite improved availability, pharmaceuticals are frequently used irrationally. The International Network for the Rational Use of Drugs (INRUD) has been established to help address this problem. The Network joins core groups of researchers from four African and three Asian countries with support groups in Boston, Sweden, WHO, and Australia. The activities of the Network are supported by multilateral, bilateral, foundation donors and by Management Sciences for Health. INRUD functions as a participatory organization in which members are involved in decision-making. The primary objective of the Network is to identify through a coordinated set of country-based research projects a set of effective interventions to recommend as policy options for the promotion of rational drug use. In developing these research projects, INRUD stresses the importance of a multi-disciplinary perspective for adequately understanding the reasons underlying inappropriate use of drugs. To better enable country groups to utilize strong research methodologies and to blend the strengths of multiple disciplines effectively, a major activity of the Network thus far has been the building of local research capacity.


The potential of transdisciplinary research for sustaining and extending linkages between the health and social sciences.

The last decade of the twentieth century is witnessing a profusion of projects drawing together social and health scientists to study and recommend solutions for a wide range of health problems. The process--practiced in both developed and developing countries--is usually called multidisciplinary or interdisciplinary research. Its historical precedents are briefly reviewed in this paper along with the types of problems addressed. From a review and discussion of a sample of projects selected from two major proponents of this approach to research, the Social and Economic Research Component of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases and the Applied Diarrheal Disease Research Project, conclusions are drawn about the nature of contributions from such efforts--very useful for short-term problem solving, less so for longer-term programmatic changes, especially beyond the health sector, and even more limited in impact on theory building for coping with the changing human condition. The recognition of such limitations is now widespread in the social and natural sciences beyond the health sector, in population, ecology, and the humanities. Following these observations, I argue for a new approach to transcend the disciplinary bounds inherent in multi- and interdisciplinary research. A transdisciplinary approach can provide a systematic, comprehensive theoretical framework for the definition and analysis of the social, economic, political, environmental, and institutional factors influencing human health and well-being. The academic and career challenges for such researchers, while considerable, may be overcome since there is now a new flexibility in research-supporting organizations to encourage new ideas in international health, such as that of essential national health research.


Local knowledge: research capacity building in international health.

Processes of building research capacity in international health projects and their implications for anthropology are addressed using examples from the Applied Diarrheal Disease Research project funded by the United States Agency for International Development. Two aspects of training are examined: the way interdisciplinary methods--qualitative and quantitative approaches--are presented to researchers, given the context of international health research culture; and how researchers' local knowledge and local concerns in pursuing health research relevant to policy led them to become interested in anthropology. The consequences for anthropology's place and product in future capacity building efforts in international health research are discussed.


Manuals for ethnographic data collection: experience and issues.

The authors' experience in developing a manual based on ethnographic methods for collecting, analyzing and using information about the 'cultural context of diarrhea' is presented. The goal of the process outlined in the manual is to recommend programmatic strategies and educational messages that are likely to be effective in achieving the adoption of appropriate diarrhea case management behaviors by mothers. The implications of manuals of this type for the role of anthropologists, and for social science capacity building in developing country programs are discussed. While recognizing that this approach risks limiting the anthropologist's role to a technical one, the authors suggest that appropriate application of program specific manuals can encourage anthropological input into formulating program policies and strategies.


Building applied health research capacity in less-developed countries: problems encountered by the ADDR Project.

As governments and other donors renew their support for research scientists in less developed countries, it becomes important to consider new questions about the process of funding scientific research and scientific researchers. This paper argues that research capacity building is a development goal subject to structural constraints and cultural impediments among both donors and recipients. Using data from one specific research capacity building program, the Applied Diarrheal Disease Research Project (ADDR), we describe a set of constraints among donors, recipient institutions, and individual recipients of research grants. We then describe how ADDR supports its investigators, how it has responded to the identified constraints, and what obstacles it still faces. Research capacity building programs in health would be well-served by focusing more attention on research problem identification, and dissemination and application of research findings.


Developing applied medical anthropology in Third World countries: problems and actions.

Recognition of the usefulness of ethnographic research in Third World community health projects and programs developed rapidly during the 1980s. As a result, the various agencies and organizations promoting community health programs (UNICEF, WHO, NGOs) have greatly increased their recruiting of social scientists, particularly medical anthropologists, for research and other programmatic activities in primary health care, child survival (especially diarrhea, acute respiratory infections, maternal and child nutrition, infectious disease, and AIDS). However, it has proved very difficult to identify well-trained anthropologists and/or other social scientists for these roles, particularly in Third World countries. This paper examines some of the background of this problem, and presents examples of methodological training (in both qualitative and quantitative research techniques) that seek to increase the skills of social scientists and other researchers in the arena of international community health.


Balancing relevance and excellence: organizational responses to link research with decision making.

Research faces the challenge of balancing relevance to decision making and excellence in the strict adherence to the norms of scientific inquiry. This paper examines the organizational responses that can be undertaken to promote integration of these potentially conflicting goals. We posit that there seem to be structural barriers to effective communication between researchers and decision makers, such as differences in priorities, time management, language, means of communication, integration of findings and definition of the final product of research. These barriers must be overcome through solutions aimed at the organization of research. In this respect, there are three possible models to approach the tension between excellence and relevance: academic subordination, segregation and integration. Only the latter makes it possible to reconcile the advantages of proximity to decision making with the procedures to assure academic quality. In addition to organizational design and institutional development, a strategy to promote research must include a set of incentives to prevent the 'internal brain drain', that is, the tendency of researchers to move to managerial positions. There are four guiding principles to address this problem: parallel careers, academic autonomy, administrative sacrifice and inverted incentives. The complexities of health problems demand that we create new organizational formulas to finally balance relevance and excellence in research.


Theory-driven behavioral intervention research for the control of diarrheal diseases.

Essentially all methods to reduce diarrheal morbidity and mortality require behavioral change. Research is required to design, implement and evaluate behavior-modifying interventions. Accumulated experience in the many involved disciplines should serve as a basis for this research. However, each of these disciplines is associated with different research perspectives and analytic assumptions; thus integration of these varied but potentially complementary experiences has been elusive. In the present paper, arguing that such perspectives and assumptions are embodied in discipline-based theory, we have developed a generic framework for the conduct of theory-based behavioral intervention research. We illustrate the application of this framework through two vignettes applying two of the theories and models to the development of hypothetical handwashing interventions.


Postoperative changes in the spinal cord in cervical myelopathy demonstrated by magnetic resonance imaging.

The relation between improvement of myelopathy achieved by surgery and postoperative spinal cord morphologic changes was investigated by magnetic resonance imaging in 51 patients with cervical myelopathy. In 22 patients, the cord indentation disappeared completely (Type I), in 23 it partially disappeared (Type II), and in 3 it remained unchanged (Type III). In three patients the cord enlarged after surgery (Type IV). With the exception of Type IV, increased restoration of cord morphology paralleled improvement in the myelopathy, suggesting that morphologic changes closely reflect neurologic recovery. In Type IV, notwithstanding the peculiar postoperative reaction, improvement was relatively good, and shrinkage of the cord enlargement was seen after 1 year. This kind of postoperative change has not been demonstrated previously by other conventional imaging methods.


Laminoplasty versus subtotal corpectomy. A comparative study of results in multisegmental cervical spondylotic myelopathy.

A comparative study of surgical results was used to determine the treatment of choice for multisegmental cervical spondylotic myelopathy. Forty-one patients who received subtotal corpectomy and strut grafting (SCS) and forty-two undergoing laminoplasty were followed up for at least 2 years after surgery. Regarding factors known to affect surgical prognosis (age at surgery, duration of symptoms, severity of neurologic deficit, anteroposterior canal diameter, transverse area of the cord at the site of maximum compression, number of levels involved), the two groups were statistically comparable with each other. The severity of neurologic deficits was assessed by the Japanese Orthopaedic Association scale. Results were evaluated in terms of postoperative score and recovery rate. The difference between the recovery rate and final score between the two groups was not statistically significant. Surgical complications were more frequent in the subtotal corpectomy and strut grafting group than in the laminoplasty group. The most frequent complications encountered in the subtotal corpectomy and strut grafting group were related to bone grafting. Spinal alignment worsened in six patients of the laminoplasty group, but none of them suffered from neurologic deterioration. Another disadvantage of subtotal corpectomy and strut grafting was the longer postoperative period of bed rest needed to secure graft stability. We conclude that laminoplasty should be the treatment of choice for multisegmental cervical spondylotic myelopathy when neurologic results, incidence of complications, and postoperative treatment are taken into consideration.


Multidirectional instabilities of experimental burst fractures of the atlas.

For the purpose of understanding the acute instability of a burst (Jefferson) fracture of the atlas, the authors produced the fractures experimentally and measured multidirectional flexibilities in seven cadaveric C0-C3 specimens. The flexibilities were measured by the authors' standardized method: they applied six types of physiologically pure moments (up to 1.5 Nm) and recorded the ensuing C0-C2 motions by stereophotogrammetry. The flexibility tests were performed before and after the production of the fracture. The greatest increase in flexibility due to the injury was in flexion-extension (+22.0 degrees, 41.7%). In lateral bending, the increase was 7.7 degrees, or 23.9%. The flexibility was mostly maintained in axial rotation (+4.8 degrees, 5.4%). The increase in motion was due to an increase in neutral zone in flexion-extension, and an increase in the elastic zone in lateral bending. These flexibility results of experimentally produced fractures reflect quite well the acute instabilities seen clinically.


Spinal cord evoked potentials in thoracic myelopathy with multisegmental vertebral involvement.

Spinal cord evoked potentials were recorded preoperatively from the thoracic epidural space after spinal cord stimulation in 20 patients with thoracic myelopathy with multisegmental vertebral involvement. Waveform abnormalities in spinal cord evoked potentials, namely, positive-going wave or decrease in amplitude, were observed in all cases. Abnormalities, especially in the first negative component of spinal cord evoked potentials, were recorded at the most compressed site in each case. Decrease in amplitude of more than 50% was noted frequently in moderately involved cases, whereas positive-going wave was elicited predominantly in cases of severe myelopathy. Spinal cord evoked potentials should provide information for determining the range of decompression in multisegmental vertebral involvement.


Rotation vector, a new method for representation of three-dimensional deformity in scoliosis.

Rotation vector for three-dimensional deformity, a new concept in scoliosis, is presented. This vector quantifies three-dimensional deformity in scoliosis. Rotation vectors are calculated between pairs of end plates. Any three-dimensional malalignments (scoliosis, lordosis [or kyphosis] and rotation) existing between a pair of end plates should be cancelled perfectly by rotating one end plate against the other about an axis represented by the rotation vector. A rotation vector suggests how the deformity in scoliosis should be corrected three-dimensionally.


Intraoperative monitoring for thoracolumbar or lumbar surgery with somatosensory evoked potentials after double stimuli.

Somatosensory evoked potentials were after double stimuli on the posterior tibial nerve for the intraoperative monitoring in 58 thoracolumbar or lumbar surgeries. The first cortical positive potential P38 and P'38 after the second stimulus was recorded after double stimuli. Transient decreased amplitude more than 50% or missing potential of P'38 was found in 11 cases. These P'38 changes occurred in five procedures of retracting the nerve roots or dural sacs, three cases of reducing of thoracolumbar fractures, and two procedures of transpedicular screwing. No causative procedure was found in one case. In those 11 cases, 5 showed no abnormality in P38 potentials and 6 cases showed less decreased amplitude in P38 than in P'38. Consequently, P'38, which was evoked by the second stimulus, can be used for the intraoperative monitoring in the thoracolumbar and lower lumbar surgery.


Pain provocation at lumbar discography as analyzed by computed tomography/discography.

Pain provocation was analyzed in 1477 intervertebral discs in 523 patients subjected to lumbar computed tomography/discography. The relation between pain provocation and the degree of general degeneration and anular disruption assessed according to the Dallas Discogram Description as indices of intradiscal deterioration was investigated. Pain provocation was also evaluated after categorizing the discs by the clinical diagnosis. Pain provocation showed little relation to intradiscal deterioration, whereas a strong relation was found between it and herniated nucleus pulposus. in herniated nucleus pulposus, discs with extraligamentous extrusion or sequestration, large protrusions, maximum protrusion site at the nerve root portion, and herniation routes passing through the central portion of the disc showed a high pain provocation ratio. Pain provocation ratios of discs associated with spinal canal stenosis were extremely low.


Pathoanatomy of lumbar disc herniation as demonstrated by computed tomography/discography.

Computed tomography/discography was performed in 378 patients (403 discs) with lumbar disc herniation receiving intradiscal therapy. The grade of disc degeneration defined by the Dallas discogram description correlated closely with age. The most common herniation routes ran through the central portion of the posterior aspect of the disc (48.9%), through the paracentral portion (18.6%) and through the entire central portion (9.7%), with these directions parallel to the sagittal plane. However, the intraforaminal and extraforaminal routes (4.2%) passed obliquely to the sagittal plane. The development of these herniation routes has been well explained by the findings of earlier histopathologic and biomechanical studies. Computed tomography/discography was very useful in observing the detailed features of HNP such as the range, site of maximum protrusion and protrusion size.


Familial predisposition and clustering for juvenile lumbar disc herniation.

The siblings and parents of 40 patients (cases) with lumbar disc herniation (aged 18 years or younger) who underwent surgery at the Department of Orthopaedics at Toyama Medical and Pharmaceutical University Hospital between 1976 and 1990 were examined for incidence of lumbar disc herniation. A total of 120 randomly sampled, age- and sex-matched patients (controls) who were hospitalized during the same period due to extraspinal diseases also were studied in the same manner. A survey of the occurrence of definite lumbar disc herniation was carried out that included 75,237 students in elementary, junior high, and senior high schools in Toyama Prefecture, Japan, covering a mean period of 3 years and 4 months. The incidence of surgically treated lumbar disc herniation among people aged 18 years or younger was calculated, and the expected value of disc herniation was obtained in an age-specific manner, on the basis of the age distribution of encumbrances in the above case-control study. The encumbrances of 18-year-old or younger patients with lumbar disc herniation showed familial predisposition, with an odds ratio of 5.61 in comparison to the controls. It was suggested that there is familial clustering of lumbar disc herniation among the encumbrances of 18-year-old or younger patients with lumbar disc herniation.


A clinical study of degenerative spondylolisthesis. Radiographic analysis and choice of treatment.

Surgical treatment of degenerative spondylolisthesis in 27 patients by means of anterior lumbar interbody fusion and in 14 patients by means of posterior decompression yielded average degrees of recovery of 77% and 56%, respectively. Preoperative analysis of myelograms, and computed tomographies after myelography indicated that anterior shifting of the inferior articular process of the slipping vertebra was the main factor responsible for compression of the nervous tissue in the early stages of degenerative spondylolisthesis. Patients in these stages should be treated by anterior lumbar interbody fusion. In the later stages of degenerative spondylolisthesis, osteophytes on the superior articular processes of the lower vertebra were an additional factor in compression, and patients should be treated by posterior decompression. Computed tomographies after myelography provided the key images for identifying pathologic processes in degenerative spondylolisthesis and selecting appropriate surgical procedures.


The mechanical properties of the human L4-5 functional spinal unit during cyclic loading. The structural effects of the posterior elements.

Cyclic axial compression-tension tests and cyclic torsional tests were performed on ten fresh human L4-5 functional spinal units to investigate the structural effects of the posterior elements on the mechanical properties of L4-5 functional spinal units. The stiffness of the functional spinal unit increased with the increase of displacement under every loading. This was same in the intact functional spinal units and the functional spinal units after removal of each posterior element, respectively. All the posterior elements contributed to the compressive, tensile, and torsional stiffness of L4-5 functional spinal units. The apophyseal joints had a significant effect on the compressive and torsional stiffness. The effect of the apophyseal joints on the torsional stiffness became greater according to the extent of displacement, whereas their effect on the compressive stiffness was constant. The posterior ligaments (supraspinous and interspinous ligaments) had a significant effect on the tensile stiffness.


Hypertrophied ligamentum flavum in lumbar spinal canal stenosis. Pathogenesis and morphologic and immunohistochemical observation.

To investigate the pathogenesis of hypertrophy of the ligamentum flavum, 45 cases of lumbar canal stenosis were evaluated by computed tomography scan and pathologic and immunohistochemical studies. The ligamentum flavum along with the medial one-third of the superior facet was obtained en bloc to include the enthesis. Statistically significant differences in transverse area and thickness of the ligamentum flavum were evident compared to the control group (P < 0.01). Pathogenesis of the hypertrophied ligamentum flavum was classified into three major groups: 1) fibrocartilage change due to proliferation of type II collagen, 2) ossification, and 3) calcium crystal deposition. It is stressed that marked proliferation of Type II collagen from the enthesis to the ligament side was revealed in the capsular portion of the hypertrophied ligament.


Experimental study of denervated muscle atrophy following severance of posterior rami of the lumbar spinal nerves.

The morphologic changes in denervation atrophy of paravertebral muscles after severance of the posterior rami in cats were investigated, using histochemical methods and electromyography. Using a paraspinal approach, three branches of the posterior rami on the left side were cut under microscopy at one, two, or three levels (L2 approximately L4). Muscle atrophy was evaluated, using the percent wet weight and the percent diameter of muscle fibers as parameters. Myosine ATPase stain was used to observe reinnervation. Four weeks after surgery, the range and severity of muscle atrophy increased proportionally to the number of posterior rami severed. Muscle atrophy was revealed at one or two levels caudal to the injured nerve level. At 12 and 24 weeks, muscle atrophy recovered gradually. In more than two-level injury groups, however, recovery of percent wet weight reached up to 80% even after 24 weeks, despite the fact of reinnervation demonstrated in some parts of the denervated muscles.


Histopathologic and morphometric study of spinal cord lesion in a chronic cord compression model using bone morphogenetic protein in rabbits.

Chronic compressive myelopathy was induced in domestic rabbits by implanting bone morphogenetic protein on the ligamentum flavum of the lumbar spine, and the resulting spinal cord lesion was studied histopathologically. In addition, morphometry of myelinated nerve fibers of the white matter in the pathologic specimens was performed to elucidate the mechanisms of cord injury. No loss of white matter nerve fibers was seen when the cord compression ratio (sagittal diameter/transverse diameter) was > 45%, although 6 months later myelin thinning was present throughout the white matter. When the cord compression ratio was < or = 45%, loss of fibers, particularly of large fibers, was seen in the superficial layer of the white matter, with the nerve fibers remaining after 6 months showing decreased diameters. No motor paresis was evident in any animal. These histologic changes represent the early pathologic condition induced by chronic cord compression.


Analysis of spinal cord evoked potential and locomotor function during acute spinal cord compression in cats.

The aim of this study was to investigate whether or not conductive spinal cord evoked potentials and spinal cord function change correspondingly with each other. The relationship between conductive spinal cord evoked potentials and locomotor function during acute spinal cord compression in animals was investigated. In decerebrate cats, controlled locomotion can be induced by electrical stimuli in the mesencephalic locomotor region. Conductive spinal cord evoked potentials were recorded at the L3 level of the spinal cord and stimuli were given at the T4 segment. The locomotor function was evaluated through electromyograms of the hind limbs. By compressing the spinal cord at L1, both the conductive spinal cord evoked potentials and the locomotor function gradually decreased. When the first negative potential amplitude of conductive spinal cord evoked potentials was decreased to half the level found in normal cats, locomotor function was injured irreversibly. These results showed that changes in the conductive spinal cord evoked potentials were related to changes in locomotor function. The 50% level of the first negative potential amplitude was considered to be the critical level at which irreversible spinal cord paralysis occurred in the cats.


The use of autologous blood in the surgical treatment of spinal disorders.

A program of autologous blood transfusion in 101 patients who underwent spinal surgery was analyzed. Autologous transfusion was achieved by intraoperative blood salvage using a cell saver and with predeposited blood. The techniques of predeposition of blood included freezing the blood and using a storage solution. Forty-eight patients had scoliosis and received mainly cryopreserved autologous blood and 53 patients had other spinal diseases. Surgery was performed using only autologous blood transfusion in more than 90% of all patients cases. The program was well tolerated by the patients and easily managed by the blood center staff. There were no severe complications associated with this program. The use of instrumentation and extensive spinal fusion were found to be factors associated with increased intraoperative blood loss. This finding suggests that instrumentation surgery and extensive spinal fusion are indications for autologous blood transfusion. Cryopreserved autologous blood transfusion is an effective method for storing a sufficient volume of blood for scoliosis surgery without affecting the patients' preoperative hemodynamic status.


The effects of hyperthermia on the spinal cord.

This study was conducted to obtain information about the critical temperature of the spinal cord in hyperthermia produced by radiofrequency waves applied to the spine. The first component of the spinal cord evoked potential was analyzed as an indicator of spinal cord function. The spinal cords were heated by radiofrequency waves to a maximum of 47 degrees C momentarily or for 30 minutes. The temperatures were measured with a thermosensor in the epidural space. In momentary heating, the reductions in amplitude were almost parallel with the increases in temperature. In maintained heating for 30 minutes, at 44 degrees C and below, the amplitudes decreased by one-quarter to three-quarters of the control value in the first 5 minutes and recovered to over three-quarters of the control value in 30 minutes. The amplitudes returned to almost the control value after restoration of normal spinal cord temperatures. At 45 degrees C and above, however, the amplitudes were prominently reduced or disappeared in the first 5 minutes and remained depressed during the remainder of the heating. On normalizing the temperature, the amplitudes did not return to the control value. These results suggest that 44 degrees C in the epidural space is the highest tolerable temperature for normal spinal cord function.


Clinical values of intraoperative ultrasonography for spinal tumors.

Intraoperative ultrasonography was conducted in 52 cases of spinal tumor, at 7.5 MHz, mainly by means of linear scanning, to evaluate its clinical usefulness. The procedure was effectively applied in such clinical purposes as: 1) locating the tumor, 2) deciding the resectability of intramedullary tumors, 3) deciding the site for intraspinal biopsy or shunt tube insertion, 4) establishing the topical relationship between the spinal cord and the tumor, and 5) differentiating neurilemoma from meningoma. Of 10 patients with intramedullary tumors, 5 (50%) were removed, because extirpation was possible when the spinal cord and the tumor were well demarcated on the ultrasonogram. Intratumorous cysts were found to exist in 73% of neurilemoma and 14% of meningioma cases, enabling the differential diagnosis between the two tumors. Intraoperative ultrasonography is an uninvasive method to reveal intradural and extradural conditions and thus constitutes a valuable diagnostic means to ensure safe and precise spinal surgery.


Magnetic coil stimulation of the spinal cord in the dog. Effect of removal of bony structure on eddy current.

Magnetic coil stimulation applied to the spine excites the lumbosacral roots rather than the spinal cord itself. To evaluate the mechanism responsible for this phenomenon, the effects of volume conduction on the activation of neural elements were studied. In ten intact dogs compound muscle action potentials could be recorded in the soleus muscle only when the magnetic coil was placed over the cauda equina. After laminectomy and pediculotomy, compound muscle action potentials also could be elicited when the magnetic coil was placed over the spinal cord. These findings suggest that the bony structure surrounding the spinal cord interferes with the spread of magnetically induced eddy currents to the spinal cord.


Standardized residuals as a means for detection of growth alteration in the pathologic human fetus.

This paper introduces and discusses the use of standardized residuals as a technique for comparing the growth of normal and pathologic human fetuses. Anthropometric measures, radiographic measures, and organ weights were regressed on known gestational age of second- and third-trimester fetuses. Standardized residuals were calculated for a group of potentially growth-impaired fetuses. Use of residuals aids in identification of patterns of growth alteration in specific pathologies. Most important, studying the response of developing organ systems to a variety of insults may elucidate mechanisms of growth regulation in the fetus. We emphasize the special quality of the multivariate measures of the core sample of fetuses from the Akron Children's Hospital collection.


Embryotoxicity studies of norfloxacin in cynomolgus monkeys. II. Role of progesterone.

Norfloxacin, an orally active fluoroquinolone antimicrobial, has been reported to be embryolethal but not teratogenic when administered to pregnant cynomolgus macaques prior to gestational day (GD) 36 at doses > or = 200 mg/kg/day. Additional studies have been performed in an effort to examine the mechanism responsible for this effect, particularly regarding the role of progesterone (P). The first study (Study I) investigated the effect of norfloxacin administration during early pregnancy (200 mg/kg/day; daily GD 20-30) in the absence of a functional corpus luteum (CL). The CL was surgically removed from 16 gravid females on GD 19 in order to focus on placental-derived P; ten were dosed with norfloxacin and six received vehicle only. Embryolethality was observed for 7/10 (70%) of the treated animals during GD 25-31 versus 0/6 (0%) for controls. A reduction in serum P was noted prior to embryonic loss, although no significant effects on chorionic gonadotropin (CG), 17 beta-estradiol (E2), or P or E urinary metabolites were observed. A second study (Study II) was performed in order to evaluate the capacity of norfloxacin (200 mg/kg) to reduce CL-derived P in both normally cycling and CG-stimulated nonpregnant females (ten treated, ten controls; daily for 8 days). No effects on P production or on luteal phase or menstrual cycle lengths were observed. The third study (Study III) was designed to examine the effect of norfloxacin on the metabolism and excretion of P in nonpregnant females. Silastic P implants were placed subcutaneously in order to maintain constant P levels during a 10 day treatment regimen (200 mg/kg/day; ten controls, nine treated). Five of the controls and four of the norfloxacin-treated females also received 14C-P intravenously within 1 hr of the last dose of norfloxacin in order to study excretory patterns. No significant differences between control and treated groups were observed. The results of these studies combined suggest that the developmental toxic effects observed in prior studies and Study I are specific to pregnancy and directly related to placental-derived P production.


Rat hepatic glutathione S-transferase-mediated embryotoxic bioactivation of ethylene dibromide.

The embryotoxic effects of ethylene dibromide (EDB) bioactivation, mediated by purified rat liver glutathione S-transferases (GST), were investigated using rat embryos in culture. Significant EDB metabolism was observed with rat liver GST purified by affinity chromatography (specific activity of 188 +/- 11.3 nmol/min/mg protein). The reaction was enzymatic in nature and the conjugation rate was proportional to the concentration of EDB (up to 0.75 mM) and the enzyme present in the reaction medium. EDB activation by 100 units (1 unit = 1 nmol of glutathione consumed per min) of purified rat liver GST caused a significant reduction in general development as measured by crown-rump length, yolk sac diameter, somite number, and the composite score for different morphological parameters (Brown and Fabro methodology). Structures most significantly affected were the central nervous and olfactory systems as well as the yolk sac circulation and allantois. The results of this study clearly indicate that under in vitro conditions, bioactivation of EDB by GST can lead to embryotoxicity.


Congenital heart disease in the offspring and maternal habits and home exposures during pregnancy.

To test the effect of maternal habits and home exposures during early pregnancy on the occurrence of congenital heart disease in the offspring, 406 cases and 756 controls were studied. The cases included all cardiovascular malformations detected in Finland during 1982-1983, while the healthy controls were randomly selected from all babies born during the same period. Case and control mothers were interviewed after delivery using a structured and pre-tested questionnaire. Maternal overall drug consumption during the first trimester was as prevalent among case mothers (13.3%) as controls (14.6%). Neither was the risk of congenital heart disease associated with maternal use of contraceptive pills, salicylates, diazepam, or sweetening agents separately. Maternal exposures to disinfectants, dyes, lacquers, paints, pesticides, or glues at home were equally prevalent in case and control groups. Several earlier miscarriages was a predictor of an infant born with congenital heart disease (OR = 2.7, CI95 = 1.4-5.3). Maternal ultrasound examination was performed during the first 16 weeks of pregnancy more often among the case group (28.3%) than among the control group (22.0%). However, the association between ultrasound examination and the risk of congenital heart disease in the offspring was not statistically significant (OR = 1.2, 95% confidence interval 0.9-1.7) when adjusted for confounding factors such as the threat of miscarriage in logistic regression analysis. It is concluded that maternal ultrasound examination, intake of some common drugs, and exposure to a number of environmental factors at home during early pregnancy are probably not harmful for the developing fetal heart.


Absence of limbs and gross body wall defects: an epidemiological study of related rare malformation conditions.

The study is based on almost 10 million births and reports on 215 infants with two unusual malformations: amelia and gross body wall defect. Amelia without body wall defect was present in 116 cases, 67 had body wall defects without amelia, and 32 had both. The total rate was 2.2 per 100,000 births. The infants were divided into five mutually exclusive groups. There were 40 infants (0.4 per 100,000) with agenesis of the body stalk, 18 with amelia and other types of gross body wall defects (0.2 per 100,000), 56 with amelia and malformations other than gross body wall defects (0.6 per 100,000), 41 with amelia (with or without other limb reduction defects) but no nonlimb malformations (0.4 per 100,000), and 60 infants with gross body wall defects of a type other than agenesis of body stalk and without amelia (0.6 per 100,000). A weak trend of decreasing prevalence of these malformations was found during the observation period. Infants with agenesis of the body stalk and infants with amelia combined with other types of gross body wall defects occurred at an increased rate in infants of young women. This maternal age effect is also found with gastroschisis, but not with omphalocele, and may indicate etiological or pathogenetic similarities between gastroschisis and the two former groups of defect. In infants with amelia, additional limb reduction defects could be of any type: transverse, longitudinal, or intercalary. Therefore, amelia may be the end result of different types of disturbances of limb morphogenesis. There was an increased rate of twinning. The relationship with amniotic band syndrome is discussed.


Association of paternal alcohol use with gestational age and birth weight.

Paternal alcohol use has been associated with a number of adverse reproductive outcomes in laboratory animals and there is one epidemiologic report of a detrimental effect on infant birth weight. To expand the epidemiologic evidence, data from the Child Health and Development Studies were analyzed. Data collected from the onset of prenatal care in 10,232 women enrolled in the Kaiser Foundation Health Plan and residing in the San Francisco East Bay area between June 1959 and September 1966 were available, including information on the mother's report of paternal alcohol consumption and a number of potential confounders. Pregnancy outcomes included preterm delivery (< 37 weeks completed gestation), moderately low birth weight (1,501-2,500 g), very low birth weight (< or = 1,500 g), small-for-gestational-age (< 10th percentile of weight for gestational age), and mean birth weight. Paternal alcohol use, analyzed in intervals from 0 to 2.0 or more drinks per day, showed no association with any of the outcomes of interest. Adjusted prevalence odds ratios ranged from 0.7 to 1.5, with no indication of a monotonic dose-response gradient. Mean birth weight was also virtually unrelated to paternal alcohol use. Compared with the earlier report, this population had a very modest level of alcohol consumption. Nonetheless, within the range that was studied there appears to be no association between paternal alcohol use and birth outcome.


Development of rat embryos in culture media containing different concentrations of normal and diabetic rat serum.

In vitro culture of rodent embryos has been extensively used in the search for teratologic agents, with possible relevance to diabetic pregnancy. However, the high concentrations of rat serum added to the culture medium (approximately 75%) have raised concern that the teratogenic effects of some compounds may be attenuated or masked in this culture system and thereby forced the addition of pharmacological concentrations of the compounds (e.g., D-glucose and beta-hydroxybutyrate) to the medium. This issue has been examined in the present study where the effects of different concentrations of rat serum on growth and differentiation of rat embryos were recorded in cultures supplemented with increased concentrations of D-glucose and beta-hydroxybutyrate. The embryonic development was also evaluated after culture in medium supplied with serum from diabetic rats. Compared with normal rat serum, the diabetic serum had an elevated glucose concentration as well as markedly increased levels of triglycerides and branched amino acids, indicating a potentially rich supply of major nutrients for the cultured embryos. Lowering the serum concentration in the culture medium from 80% to 50% yielded progressively retarded embryonic growth but no increased rate of other morphological malformations. At 40% serum concentration, however, there was a sharp rise in the incidence of somatic malformations, in addition to the prevailing growth retardation. When the embryonic growth and development were compared at 50% and 80% serum concentrations, increased D-glucose or beta-hydroxybutyrate concentrations caused similar degrees of embryonic dysmorphogenesis. Also, the uptake of each compound by the embryos exposed to elevated levels of the two agents were similar in 50% and 80% serum cultures. There was, therefore, no protection against the teratogenic and growth-retarding effects of increased D-glucose or beta-hydroxybutyrate offered by high serum concentrations in the culture medium (i.e., 80% vs. 50%). Embryos cultured in 50% or 80% diabetic rat serum at 30 mmol/L or 50 mmol/L D-glucose concentration showed similar rates of somatic malformations as did embryos exposed to the same proportion of normal rat serum at similar glucose concentrations. By contrast, the diabetic rat serum amplified the general retarding effects of high D-glucose levels, yielding lower protein levels and somite numbers in embryos from diabetic serum culture than in embryos cultured in normal rat serum.(ABSTRACT TRUNCATED AT 400 WORDS)


Histopathological and hemodynamic studies supporting hypoxia and vascular disruption as explanation to phenytoin teratogenicity.

The limb plates and craniofacial regions in rabbit fetuses were examined shortly after the last dose of phenytoin on day 16 after daily administration by gavage with either 150 mg/kg on days 14-16 or 300 mg/kg on days 15-16. Both treatment regimens resulted in similar changes. Histologically, the digital areas of the limb plates showed extensive edema and dilated blood vessels within 2 h. After 8 h, vascular disruption occurred with hemorrhages. At 24-48 h after dosing, mesenchymal necrosis and, on some occasions, amputation of digits was observed. In the craniofacial region, well-defined superficial hemorrhage was seen in the frontal and nasal region at 8 h. Histologically, subectodermal hemorrhage caused by vascular disruption and microfocal mesenchymal necrosis was observed. At 48 h, some fetuses showed severe diffuse intracranial and superficial hemorrhage, resulting in massive tissue damage, also in the central nervous system (CNS). Maternal heart rate, blood pressure, PO2, and PCO2 were also measured in awake pregnant rabbits 6 h after the last dose on day 16 after daily administration with 150 mg/kg during gestational days 14-16. An attempt was also made to measure fetal heart rate in anesthetized rabbits. The maternal heart rate and blood pressure decreased with about 15% in phenytoin-treated animals, resulting in a decrease in PO2 (approximately 15%) and an increase in PCO2 (approximately 15%). A decrease in fetal heart rate was also registered. The results thus indicate that phenytoin exerts its teratogenic effects by inducing fetal hypoxia, leading to vascular disrupture and necrosis of existing and developing structures.


Methionine decreases the embryotoxicity of sodium valproate in the rat: in vivo and in vitro observations.

Methionine provided in the drinking water of pregnant rats injected with sodium valproate reduced the frequency of resorptions but did not improve embryo growth. Rats drinking methionine supplemented water had approximately twice the level of serum-free methionine and consumed only one-half the volume of water of controls. Using whole rat embryo cultures, the simultaneous addition of methionine and sodium valproate to the medium provided no protection from neural tube defects, nor did the addition of methionine to a medium of serum obtained from rats previously dosed with sodium valproate. However, protection from the teratogenic effects of sodium valproate was afforded by methionine when the culture medium was sera from rats consuming methionine and was particularly striking when embryos for culture were taken from pregnant rats that had been consuming methionine. These observations along with those of others indicated the importance of dietary and culture media methionine levels in evaluating experimental and regulatory teratology studies and suggested the possibility that methionine may play an important role in human teratology where multifactorial causes have been implicated in problems such as neural tube closure defects.


Histochemical and immunohistochemical distribution of glycosaminoglycans, type II collagen, and fibronectin in developing fetal cartilage of congenital osteochondrodysplasia rat (ocd/ocd).

The osteochondrodysplasia rat (ocd/ocd) is a lethal dwarfism. The ocd/ocd shows histological abnormalities of the epiphysis, characterized by a decrease in amount of glycosaminoglycans (GAGs) in the extracellular matrix (ECM). The present study describes histochemical and immunohistochemical distributions of GAGs, type II collagen, and fibronectin (FN) in abnormal humeral cartilage of the ocd/ocd fetuses on days 16-21 of gestation. A wide-spread region with severe necrosis was observed in the cartilage on days 20 and 21. The affected cartilage has small amounts of ECM, irregular columnizations, thinner hypertrophic zones, and expanded and pyknotic chondrocytes on days 16-21 of gestation. The severely expanded chondrocytes did not have cytoplasmic glycogens on days 19-21. Reactions for chondroitin sulfate (CS) and hyaluronic acid (HA) in the ECM were consistently lower in ocd/ocd than in +/+ during the entire period of observation, although there were granules immunoreactive to CS within the chondrocytes of ocd/ocd. The distribution of type II collagen seemed normal in relatively normal regions in the affected cartilage. Strong reactions for CS, HA, type II collagen, and FN were present in the necrotic region on days 20 and 21 of gestation. These findings suggest that the affected chondrocyte may have some defects in releasing ECM substances, which may be released by the process of cell rupture. We hypothesize that some defects in releasing processes inherent to the ocd/ocd cartilage may relate to cellular differentiation and cell death.


Prevalence of human immunodeficiency virus infection in hospitalized adults at a teaching hospital in west Texas.

The prevalence of infection with human immunodeficiency virus (HIV) among hospitalized adults at a teaching hospital in West Texas was estimated by conducting a serological survey. Of the 2,458 patients tested, 12 (0.5%) were seropositive. All 12 were men of ages 28 through 50 years; 11 were white and 1 was Hispanic. Eleven were previously known to be HIV positive and were hospitalized for illnesses related to acquired immunodeficiency syndrome (AIDS). All seropositive patients were hospitalized on nonsurgical services of internal medicine, medical-surgical neurology, and family practice. These results indicated that the sampled population in West Texas showed a relatively low prevalence of HIV infection and that seropositive patients were predominantly white men hospitalized for AIDS-related illnesses.


Risk factors for infection with human immunodeficiency virus among low-income women undergoing voluntary sterilization.

Data regarding risk for infection with human immunodeficiency virus (HIV) were collected from 486 women who presented in 1989 for tubal sterilization through a clinic operated by a medical school. This clinic was participating in a blind surveillance project administered by the local health department. The project was designed to estimate the prevalence of seropositivity for HIV among women seeking family planning services within the department's catchment area. The expectation was that the population of women choosing voluntary sterilization would be of relatively low risk for HIV infection. Surprisingly, however, when they were examined, nearly 25% of these women reported at least one identified risk factor for HIV infection. The rates for certain specific risk factors are no lower among these women than among the general population.


Approaching families for organ donation: physicians are willing.

While current literature documents a critical disparity between the increasing demand for organs for transplantation and the relatively static supply, reasons for the shortage of donors are not well understood. Public opinion surveys describe a population willing to donate, but consent rates reported by organ procurement organizations suggest problems in the process of approaching families. This study of Texas physicians regarding their knowledge of laws related to brain death and to routine inquiry for organ donation and their attitudes toward the critical step of seeking consent from families indicates that physicians need more information about questions asked by families, would benefit from more structured hospital policies on routine inquiry, feel that physicians rather than nurses should approach families, and believe that the public is not well informed about donation.


Health expenditures in Texas, 1988.

Expenditures for health care in Texas during 1988 totaled $32.4 billion. Health spending by category of service and sources of payment was estimated and compared with estimates for prior years and with national trends. Texas differed from the nation as a whole in average annual increases in total spending, the percentage of spending for prepayment and administration, and the percentage of spending paid by consumers, the federal government, and private insurance. Proposed expansions in insurance coverage for the large proportion of uninsured Texans will probably require strong efforts to contain costs.


Relationship between the immune system and the diseases of the central nervous system.

Considering the eventual role of non-specific cell-mediated immune reactions in the pathogenesis of Parkinson's syndrome based on the destruction of dopaminergic cells of the substantia nigra the killer cell activity of patients suffering from this disease has been examined. According to the results the killer cell activity of Parkinson patients is significantly lower in the age group below 60 years as compared to the higher age groups. When comparing the age groups below 60 years, significantly lower activity was measured in the patients than in the controls. Killer cell activity is significantly higher in patients suffering from more severe conditions (Hoehn-Yahr's stage IV-V) when compared to the milder cases. These results suggest the possibility that killer cell-mediated ADCC reaction may play a role in the pathogenesis of the disease. The results of these examinations open new therapeutic perspectives. It may be hoped that, as a result of our increasing knowledge and technical progress in immunology, the damaged immune system could be selectively influenced and target specific immune therapy could be used in the near future by means of for instance inactivations of cytotoxic cells, elimination of antibodies or other immunological methods.


Anti-anginal effect of Tenormin (atenolol).

The anti-anginal effect of Tenormin (atenolol) has been examined besides placebo control by single blind method in 20 patients with ischaemic heart disease, suffering from stable effort angina proved by coronarography. It has been observed that atenolol significantly decreases the weekly number of anginal attacks, and the amount of sublingual nitroglycerin consumption. It has been proved that atenolol successfully prevents the exercise-induced elevation of blood pressure and heart rate, increases exercise tolerance, decreases myocardial O2 consumption. The place among beta-blockers of the cardioselective, low lipophilic atenolol, which lacks membrane stabilizing and partial agonist activity, has been discussed. The administration of a single daily dose (one 100-mg tablet), selective cardiac effect, lack of unwanted side-effects (cold extremity, nightmare, insomnia, etc.) are the advantages of the drug.


Several years observations with Mydocalm muscle relaxant in locomotor disease patients.

Two therapeutic methods were compared on locomotor disease patients; the currently used anti-inflammatory complex therapy and the same therapy complemented with Mydocalm. On the basis of the changes of pain indices and motion indices chosen as parameters it could be concluded that Mydocalm is a valuable adjuvant, especially in improving locomotor functions, and it promotes the improvement of the general condition of the patients and the performance of their daily activities by relieving muscular hypertonia and contractures.


Use of pefloxacin in urogenital infections.

Forty-three patients suffering from acute or chronic urinary tract infections have been treated with pefloxacin at the Department of Urology of St. Istán Hospital. Twenty-three patients received oral doses (2 x 400 mg), 1 tabl. in the mornings and 1 in the evenings. Eighteen patients were given 2 x 1 intravenous ampoule (2 x 400 mg) dissolved in 250 ml 5% glucose in slow drip infusion. Both the oral and intravenous doses were given in the patients for 10 days. In two patients complications was observed--in one case rhagades were formed on the lip and face due to photo-sensibilization, in the other case the drug administration had to be discontinued because of nausea and vomiting. These symptoms ceased after the discontinuance of the drug. The clinical conditions, the routes of administration, clinical and bacteriological results are summarized in tables. On the basis of a low number of cases it has been concluded that pefloxacin is a new valuable antibacterial drug the use of which resulted in recovery in 15 out of 18 patients' acute and chronic infections of the urogenital system.


Haemodynamic effect of nitroglycerin spray.

1. It is a reliable nitroglycerin (NTG) form influencing circulation and haemodynamics like other nitroglycerin products, 2. It is easily applicable, 3. Its use is advantageous especially for the prevention of pressure elevation occurring in response to physical exercise thus for the prevention of effort angina as well, 4. It is a reliable drug to be used in haemodynamic laboratories for measuring nitroglycerin effect, 5. Due to the rapidly developing fall of end diastolic pressure caused by the product it is also of value in controlling cardiac asthma attacks.


Estulic--a well tolerated and effective antihypertensive drug in general practice.

The results of the treatment of 28 patients with mild to moderate hypertension using guanfacin (Estulic) monotherapy and of 24 patients receiving combined antihypertensive therapy containing Estulic are reported on. The blood pressure was lowered and stabilized during the first month of therapy. No addiction or loss in effectivity was seen. There were no changes in ECG or laboratory results during the mean follow up time of 11 months. Four patients discontinued the drug because of subjective side-effects. The single daily dose, the reliable effectivity, the safety of the drug makes it an important antihypertensive drug in general practice.


Mydocalm treatment of muscular and vascular complaints accompanying climacterics.

Coated Mydocalm tablet, known as striated muscle relaxant and peripheral vasodilator, has been used in climacteric women. The women suffered from muscular and vascular complaints besides the common symptoms of decreased or lacking ovarian function which could not be controlled with oestrogen substitution therapy. Mydocalm significantly moderated these complaints without causing unwanted effects and the majority of the women could be maintained in a complaint-free condition in this respect. According to the opinion of the author the drug is a valuable adjuvant to an adequate hormone therapy.


Observations with a tri-phasic oral contraceptive (Tri-Regol) in everyday clinical practice.

The theoretical general principles of triphasic oral contraception are discussed in the introduction. This method, which is the closest to a physiological dosage, seems to be the most advantageous today. International data and the advantages and wide indication field of such "step-up" tablets are also discussed. The observations with the Hungarian Tri-Regol tablet are described in detail. In the course of controlling 355 cycles of 79 women pregnancy was not observed, the tablets were well tolerated by the women-except for some milder side-effects. The use of Tri-Regol needed not be discontinued due to, any unwanted effect or complication. The rate of intermenstrual bleeding was very low, and the triphasic therapy proved to be beneficial in case of manifesting cycle disorders or if the change of the contraceptive tablet became necessary because of intolerance. According to the opinion of the authors the oral contraceptive Tri-Regol is today's drug of choice due to its reliable ovulation inhibitory action, low hormone content, and favourable tolerability.


Some indications for the gynaecological use of budesonide (Apulein).

Budesonide-containing Apulein ointment has been used for the treatment of 29 women suffering from vulvitis, pruritus vulvae caused by vaginal discharge, gestational inflamed hemorrhoid, hymenitis, and late postoperative suture inflammation. The ointment rapidly and completely controlled local infiltration and the accompanying subjective complaints. It did not cause local alteration, the consistency of the ointment met the requirements and it did not disturb the patients' making their toilet. According to the author's opinion the product is a potent antiphlogistic which proved to be a valuable adjuvant to target specific treatment of inflammatory processes of the external female genital organs and perianal regions.