Nocturnal Enuresis in India: Are We Diagnosing and Managing Correctly?

Nocturnal enuresis is a common problem affecting school-aged children worldwide. Although it has significant impact on child's psychology, it is always under-recognized in India and considered as a condition which will outgrow with advancing age. Nocturnal enuresis classified as primary or secondary and monosymptomatic or nonmonosymptomatic. Factors that cause enuresis include genetic factors, bladder dysfunction, psychological factors, and inappropriate antidiuretic hormone secretion, leading to nocturnal polyuria. Diagnosis consists of detailed medical history, clinical examination, frequency-volume charts, and appropriate investigations. The frequency-volume chart or voiding diary helps in establishing diagnosis and tailoring therapy. The first step in treating nocturnal enuresis is to counsel the parents and the affected child about the condition and reassure them that it can be cured. One of the effective strategies to manage enuresis is alarm therapy, but currently, it is not easily available in India. Desmopressin has been used in the treatment of nocturnal enuresis for close to 50 years. It provides an effective and safe option for the management of nocturnal enuresis. This review covers the diagnosis and management of nocturnal enuresis and introduces the concept of "bedwetting clinics" in India, which should help clinicians in the thorough investigation of bedwetting cases.

Topical lincomycin gel in acne vulgaris: a multicentric placebo controlled study.

INTRODUCTION: Acne vulgaris is commonly treated with topical antibacterials. We evaluated lincomycin gel, a new topical formulation for mild to moderate acne. MATERIAL AND METHODS: A multicentric, randomized, double blind, placebo controlled, clinical trial was conducted with lincomycin hydrochloride in 2% gel form in 200 patients with grade II and grade III acne. The severity of acne lesions was noted at baseline and after 4 weeks. RESULTS: About 70% cases in the study group showed a good to excellent response, which was significantly more as compared to 23% in the placebo group. The frequency and severity of adverse reactions in the two groups were similar. CONCLUSION: Lincomycin hydrochloride gel is an effective and safe treatment option for mild to moderate acne vulgaris.

Significance of histopathological classification in leprosy.

A retrospective blind study was carried out on 2640 patients of leprosy to correlate the histopathological and clinical classification of leprosy using the criteria laid down by Ridley and Jopling. There was complete agreement between histopathological and clinical classification in 81.8% of the cases, with one step deviation in 5.1% of the cases. Histopathological diagnosis of indeterminate leprosy in high percentage (15.9%) as against 3.3% of indeterminate leprosy clinically in our series was an interesting feature. Type-wise correlation between histopathological with clinical classification was very high, it being the highest in LL (98%) followed by TT (97%), BT, BB and BL (95%, 89% and 87% respectively).

Cysteine 42 is important for maintaining an integral active site for O-acetylserine sulfhydrylase resulting in the stabilization of the alpha-aminoacrylate intermediate.

O-Acetylserine sulfhydrylase-A (OASS-A) is a pyridoxal 5'-phosphate (PLP) dependent enzyme from Salmonella typhimurium that catalyzes the beta-replacement of acetate in O-acetyl-L-serine (OAS) by sulfide to give L-cysteine. The reaction occurs via a ping-pong kinetic mechanism in which alpha-aminoacrylate in Schiff base with the active site PLP is an intermediate [Cook, P. F., Hara, S., Nalabolu, S. R., and Schnackerz, K. D. (1992) Biochemistry 31, 2298-2303]. The sequence around the Schiff base lysine (K41) has been determined [Rege, V. D., Kredich, N. M., Tai, C.-H., Karsten, W. E., Schnackerz, K. D., & Cook, P. F. (1996) Biochemistry 35, 13485-13493], and the sole cysteine in the primary structure is immediately C-terminal to the lysine. In an effort to assess the role of C42, it has been changed to serine and alanine by site-directed mutagenesis. The mutant proteins are structurally nearly identical to the wild-type enzyme on the basis of UV-visible, fluorescence, far-UV and cofactor-induced CD, and 31P NMR studies, but subtle structural differences are noted. Kinetic properties of both mutant proteins differ significantly from those of the wild-type enzyme. The C42S mutant exhibits a > 50-fold increase in the OAS:acetate lyase activity and a 17-fold decrease in V for the cysteine synthesis compared to the wild-type enzyme, while decreases of > 200-fold in the OAS: acetate lyase activity and a 30-fold decrease in V for the cysteine synthesis are found for the C42A mutant enzyme. In both cases, however, the pH dependence of kinetic parameters for cysteine synthesis and OAS: acetate lyase activity yield, within error, identical pK values. In the three-dimensional structure of OASS-A, cysteine 42 is located behind the cofactor, pointing away from the active site, toward the interior of the protein. The dramatic change in the OAS:acetate lyase activity of OASS-A in the C42S and C42A mutant proteins likely results from a localized movement of the serine hydroxyl (compared to the cysteine thiol) toward additional hydrophilic, hydrogen-bonding groups in C42S, or away from hydrophilic groups for C42A, repositioning structure around and including K41. Subtle movement of the epsilon-amino group of K41 may change the geometry for nucleophilic displacement of the amino acid from PLP, leading to changes in overall activity and stability of the alpha-aminoacrylate intermediate. Data indicate that single amino acid substitutions that yield only subtle changes in structure can produce large differences in reaction rates and overall mechanism.

Phase I trial of weekly paclitaxel in advanced lung cancer.

PURPOSE: We conducted a phase I study in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose (MTD) of paclitaxel using an extended weekly schedule. PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were treated with paclitaxel administered weekly over 3 hours for 6 weeks of an 8-week cycle. Doses were modified for granulocyte counts less than 1,800/microL or neurotoxicity greater than grade I. Groups of three patients were entered at each dose level. The dose was escalated to the next level if less than 50% of patients developed unacceptable toxicity and received more than 80% of the intended first-cycle dose. RESULTS: Twenty-six patients were entered through six dose levels (100, 125, 135, 150, 175, and 200 mg/m2/wk). Four of six patients at the 175-mg/m2 dose level and only one of six patients at the 200-mg/m2 level received all scheduled doses of paclitaxel during cycle 1. Neutropenia was dose-limiting. Fourteen patients were treated with subsequent cycles of paclitaxel. Grade II to III neuropathy developed in five of 24 patients. It occurred more commonly with greater duration of therapy, but improved following dose reduction. Nine of 26 (35% +/- 10%) patients demonstrated an objective response. CONCLUSION: The MTD of paclitaxel using a weekly schedule is 175 mg/m2/wk for 6 of 8 weeks. Neutropenia limits dosing acutely, but neuropathy is limiting with sustained therapy. This schedule of paclitaxel results in a twofold to threefold increase in dose-intensity with less toxicity than anticipated from conventional dosing. Further evaluation of this schedule is warranted to assess efficacy and toxicity of prolonged administration.

Weekly paclitaxel in patients with advanced lung cancer: preliminary data from a phase II trial.

We conducted a phase II trial in chemotherapy-naive patients with advanced non-small cell lung cancer to determine the efficacy of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) delivered at a maximum tolerated dose of 175 mg/m2 on an extended weekly schedule. Patients with stage IIIB/IV non-small cell lung cancer were eligible if they had an Eastern Cooperative Oncology Group performance status of 0 to 2, had received no previous chemotherapy, demonstrated normal hematologic and hepatic function, and could provide informed consent. Paclitaxel 175 mg/m2 was administered as an intravenous infusion weekly over 3 hours with standard premedication, for 6 weeks of an 8-week cycle. Doses were modified for absolute neutrophil count less than 1.5 x 10(9)/L or neuropathy greater than grade I on the day of therapy. Patients without progressive disease received subsequent cycles at the same dose. To date, 30 patients have been enrolled; data are available for 25. The median age was 65 years (range, 38 to 78 years), 23 patients were performance status 0 or 1, and 14 had received prior radiation. Sites of disease included the lung (23 patients), central nervous system (11), bone (seven), liver (one), kidney (one), and soft tissue (eight). Eighty-three percent, 75%, 58%, and 50% of intended doses were delivered during cycles 1 though 4, respectively. Grade 2/3 neuropathy occurred in nine patients, but improved in all nine following dose reduction. Grade 3/4 neutropenia occurred in 10 patients. Partial responses occurred in 14 of 25 patients (56%; 95% confidence interval, 46% to 66%). Median duration of response was 6.5 months, and the 1-year survival rate was 53%. The extended weekly paclitaxel schedule results in enhanced dose intensity, marked activity, and acceptable toxicity. Paclitaxel given weekly at maximum dose intensity may be more effective than conventional paclitaxel administration schedules.

A change in the internal aldimine lysine (K42) in O-acetylserine sulfhydrylase to alanine indicates its importance in transimination and as a general base catalyst.

O-Acetylserine sulfhydrylase (OASS) is a pyridoxal 5'-phosphate dependent enzyme that catalyzes a beta-replacement reaction forming L-cysteine and acetate from O-acetyl-L-serine (OAS) and sulfide. The pyridoxal 5'-phosphate (PLP) is bound at the active site in Schiff base linkage with a lysine. In the present study, the Schiff base lysine was identified as lysine 42, and its role in the OASS reaction was determined by changing it to alanine using site-directed mutagenesis. K42A-OASS is isolated as an external aldimine with methionine or leucine and shows no reaction with the natural substrates. Apo-K42A-OASS can be reconstituted with PLP, suggesting that K42 is not necessary for cofactor binding and formation of the external Schiff base. The apo-K42A-OASS, reconstituted with PLP, shows slow formation of the external aldimine but does not form the alpha-aminoacrylate intermediate on addition of OAS, suggesting that K42 is involved in the abstraction of the alpha-proton in the beta-elimination reaction. The external aldimines formed upon addition of L-Ala or L-Ser are stable and represent a tautomer that absorbs maximally at 420 nm, while L-Cys gives a tautomeric form of the external aldimine that absorbs at 330 nm, and is also seen in the overall reaction after addition of primary amines to the assay system. The use of a small primary amine such as ethylamine or bromoethylamine in the assay system leads to the initial formation of an internal (gamma-thialysine) or external (ethylamine) aldimine followed by the slow formation of the alpha-aminoacrylate intermediate on addition of OAS. Activity could not be fully recovered, and only a single turnover is observed. Data suggest a significant rate enhancement resulting from the presence of K42 for transimination and general base catalysis.

A randomized phase II study of ifosfamide/mesna/cisplatin plus G-CSF or etoposide/cisplatin plus G-CSF in advanced non-small cell lung cancer: a Cancer and Leukemia Group B study.

This Phase II study was designed to determine the efficacy of two chemotherapy regimens with G-CSF support for patients with advanced non-small cell lung cancer (NSCLC). One-hundred and one patients with Stage IIIB or IV NSCLC and performance status 0-1 were randomized to receive ifosfamide 2.0 g/m2 days 1-3, mesna 400 mg/m2 at 0, 4, 6 h days 1-3, cisplatin 33 mg/m2 days 1-3 or etoposide 200 mg/m2 days 1-3, cisplatin 35 mg/m2 days 1-3. Both groups received G-CSF 5 micrograms/kg SQ day 4 to the post day 11 absolute neutrophil count > 10 000. For the 47 eligible patients receiving ifosfamide/mesna/cisplatin, the response rate was 26% (95% confidence interval: 14-40%) and the median survival 7.5 months (95% confidence interval: 5.8-11.0 months). Grade 3 or worse toxicities were: neutropenia 75%, thrombocytopenia 70%, infection 21%. There were two treatment-related deaths due to infection. For course 1, the median absolute neutrophil count nadir was 1.3, platelet nadir 96 000 and incidence of febrile neutropenia 16%. For the 48 eligible patients receiving etoposide/cisplatin, the response rate was 21% (95% confidence interval: 11-35%) and median survival 5.8 months (95% confidence interval: 4.5-9.7 months). Grade 3 or worse toxicities were: neutropenia 90%, thrombocytopenia 58%, infection 29%. There were three treatment-related deaths due to infection. For course 1, the median absolute neutrophil count was 0.2, platelet nadir 80 000 and incidence of febrile neutropenia 33%. For both ifosfamide/mesna/cisplatin and etoposide/cisplatin, median duration of Grade IV neutropenia was short (< or = 4 days), time to subsequent courses 21 days and dose delivered > 95% of planned dose. Although G-CSF allowed full doses of drugs to be delivered on schedule, both ifosfamide/mesna/cisplatin and etoposide/cisplatin produced response rates and survival similar to other cisplatin-based regimens. In view of the significant cost of G-CSF and no obvious improvement in response rate, survival or toxicity profile, G-CSF cannot be recommended with these chemotherapy regimens for patients with advanced NSCLC.

Comparison of Kodak Amerlite FT4 and TSH-30 with T4 and TSH as first-line thyroid function tests.

OBJECTIVES: To evaluate the effect of test automation and a change in strategy for thyroid function tests (TFT) on personnel needs and turn-around time. The first-line TFT were changed from T4 and TSH to FT4 and TSH-30. DESIGN AND METHODS: Samples received for TFT from 357 randomly selected patients were analyzed by RIA for T4, and by IRMA for TSH as first-line tests. FT3 and TBG were requested as back-up tests when indicated. Patients were classified on the basis of these results and the clinical information received. All the samples were reanalyzed for FT4 and TSH on the Amerlite Processing Center, which is a batch, semiautomated immunoassay system. The thyroid status of the patients was compared using the two protocols and available clinical data. RESULTS: There was good correlation between TSH-IRMA and TSH-30 in the 160 patients classified as euthyroid (r = 0.956; p < 0.001) and no euthyroid patient was reclassified with the new strategy. In 21 patients with borderline raised TSH-IRMA, FT4 was found to be low in only 2. All 11 patients classified as hypothyroid had TSH results greater than 10 mU/L and all except 2 patients had FT4 less than 11 nmol/L. The status of 21 hyperthyroid as well as 40 patients on carbimazole could be determined biochemically on the basis of agreement between both the FT4 and TSH-30 results. FT3 was only required if the FT4 and TSH-30 results were not in agreement. In 42 patients on T4 therapy, adequacy of replacement was assessed better using FT4 and TSH-30. No patient required backup testing with TBG to determine thyroid status using the new testing protocol. The change in TFT protocol reduced the 95% turn-around time from 3 days to 1 day. CONCLUSION: The introduction of FT4 and TSH-30 as first-line TFT improved the turn-around time for TFT, resulted in 25% reduction in personnel requirements, 60% reduction in FT3 assays, and discontinuation of TBG assay.

Treatment of reiter's disease.

Two classical cases of Reiter's disease, one successfully treated with methotrexate and the other with sulphasalazine are reported.

Treament of bechcet's disease.

A case of Behcet's disease treated initially wiht corticosteroids to which dapsone was added subsequently and being kept in remission with dapsone alone is presented. High maintenance dose of corticosteroids necessitated the substitution with dapsone.

Thyroid antoantibodies and the response to thyrotropin releasing hormone in patients with subclinical hypothyroidism.

AIM: To evaluate the clinical usefulness of the thyrotropin releasing hormone (TRH) test and estimation of thyroid autoantibody concentrations in patients with borderline raised thyroid stimulating hormone (TSH). METHODS: The records of 34 consecutive patients with persistent borderline increased TSH (4.4-9.9 mU/l) referred to the Medical Investigation Unit were reviewed. The response of patients with thyroid autoantibodies to the TRH test was compared with that of patients with a negative antibody screen. RESULTS: Eleven (44%) of 25 patients with positive anti-thyroid microsomal and/or thyroglobulin antibody tests and three (33%) of nine patients with a negative antibody screen had hypothyroid responses to TRH. Neither age nor sex affected the response to TRH. Basal TSH alone was poorly correlated with these indices. Twelve (35%) patients who had elevated basal TSH had a normal response to the TRH test. CONCLUSION: Patients with positive or negative thyroid autoantibodies and an exaggerated response to the TRH test should be regarded as hypothyroid and treated with thyroxine. Patients with positive thyroid autoantibodies and normal TSH response may subsequently develop hypothyroidism and should be given long term follow up.

Phenytoin therapy in recessive dystrophic epidermolysis bullosa.

A case of recessive dystrophic epidermolysis bullosa in a 17-year-old boy is described. The diagnosis was based on clinical and histophathological findings. The patient is being treated with 200-300 mg of phenytoin sodium per day maintaining a blood level of 13-15 mg/litre and is under remission for 1 year.

Treatment of Reiter's disease.

Two classical cases of Reiter's disease, one successfully treated with methotrexate and the other with sulphasalazine are reported.

Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel administered weekly on an outpatient basis with concurrent thoracic radiation to patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this phase I clinical trial, paclitaxel was administered as a 3-hour intravenous (IV) infusion, repeated every week for 6 weeks. The starting dose of paclitaxel was 10 mg/m2. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients if tolerated. Unacceptable toxicity was defined as grade 3 nonhematologic toxicity, excluding nausea and vomiting, and grade 4 hematologic toxicity according to Cancer and Leukemia Group B expanded common toxicity criteria. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). RESULTS: Twenty-seven patients were entered onto this study through seven dose escalations (from 10 mg/m2/wk to 70 mg/m2/wk for 6 weeks). Severe esophagitis occurred at 70 mg/m2 (two patients with grade 4 disease and one patient with grade 2). One of six patients at 60 mg/m2 developed grade 3 esophagitis and three of seven patients had grade 2 esophagitis. One of 27 patients developed a hypersensitivity reaction. One of 27 patients developed grade 3 neutropenia. CONCLUSION: Esophagitis is the principle dose-limiting toxicity of weekly paclitaxel and thoracic radiation in the outpatient setting. A phase II trial using concurrent radiation and paclitaxel at the MTD of 60 mg/m2/wk is underway.

Dapsone syndrome in Goa.

Daspone syndrome was noted within six weeks of starting treatment in 1.3% of about 700 leprosy patients on MDT reporting to the skin department of Goa Medical College. Skin rash, photosensitivity, fever, lymphadenopathy, sore throat, hepatosplenomegaly, abnormal liver function tests and raised reticulocyte count were consistent features in all the patients. Other drugs, infectious mononucleosis and viral exanthemata were considered in differential diagnosis. Withdrawal of dapsone and administration of prednisolone controlled the condition within three to four weeks in majority of the patients. One patient died of ischemic heart disease unrelated to dapsone syndrome.

Osteomyelitis presenting as genital sore: a case report.

A female attending the skin outpatient department presented with a genital sore which was treated as chancroid. On further investigation it proved to be the opening of a sinus secondary to chronic osteomyelitis of the pubic symphysis.