Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter 2 Inhibitors: Clinical and Biochemical Characteristics of 29 Cases.

Objective: To describe the clinical and biochemical characteristics of all reported cases of DKA associated with SGLT2 inhibitor use in patients with type 2 diabetes mellitus and to identify potential risk factors. Design: A retrospective case series was conducted between March 2013 and August 2019 using an electronic medical record search algorithm. Results: 25 patients met the criteria for DKA associated with SGLT2i use (total of 29 cases), 15 were female, average age was 54.24 years, and mean diabetes duration was 8.76 years. The majority of the patients (23 patients) had no history of prior DKA. Average blood glucose concentrations at presentation were 298.9 ± 152.7 mg/dl. Interestingly, nearly half of the episodes (14) met the criteria of euglycemic DKA (glucose <250 mg/dl). Average anion gap values were 26.59 ± 6.15 mg/dl, bicarbonate values were 11.14 ± 5.57 mg/dl, and pH values were 7.16 ± 0.12. All had positive serum and urine ketones. The most common presenting symptoms were nausea, vomiting (18 cases), and abdominal pain (10 cases). Common precipitants were poor oral intake (18 cases) and infection (10 cases). A variety of drugs were prescribed along with an SGLT2i, and 11 of the patients were using insulin. None of the cases were fatal. Comparison between euglycemic DKA and hyperglycemic DKA did not identify any significant difference. A major limitation factor of the study was the lack of control group or comparison to other antiglycemic agents to assess the relative risk. Conclusions: The majority of SGLT2i-associated DKA cases occurred in patients with T2DM without prior episodes of DKA. The most common presenting symptoms were nausea, vomiting, and abdominal pain, while poor food intake and infection were the main precipitants. Clinicians should consider the possibility of DKA in SGLT2i-treated patients presenting with these symptoms, even in absence of marked hyperglycemia.

Brief report: Aggressive challenging behaviour in adults with intellectual disability following community resettlement.

BACKGROUND: Aggressive challenging behaviour is common in adults with intellectual disability (ID) in long-term care facilities. The government's commitment to the closure of all facilities in England has led to concerns over how to manage this behaviour in the community. The aim of this study was to assess changes in aggressive challenging behaviour and psychotropic drug use in adults with ID following resettlement using a person-centred approach. METHOD: The Modified Overt Aggression Scale was administered to carers of 49 adults with ID prior to discharge from a long-stay hospital and 6 months and 1 year after community resettlement. RESULTS: All areas of aggressive challenging behaviour reduced significantly between baseline and 6 months following resettlement (P < 0.001). This reduction remained (but did not decrease further) at 1-year follow-up. CONCLUSIONS: Further work is needed to evaluate the role of environmental setting on aggressive challenging behaviour in adults with ID.

Single Injection Technique Prolotherapy for Hypermobility Disorders of TMJ Using 25 % Dextrose: A Clinical Study.

INTRODUCTION: Hypermobility disorders of the Temporomandibular joint (TMJ) can be treated by both conservative and surgical approaches. Conservative approaches should be considered as first line treatment for such disorders. Prolotherapy with 25 % dextrose being injected into the posterior pericapsular tissues is one such treatment modality with favorable outcomes. AIM: To study the efficacy of single injection of 25 % dextrose in pericapsular tissues in the management of hypermobility joint disorders of TMJ as first line treatment. PATIENTS AND METHODS: We have studied a total of 23 patients suffering from either chronic recurrent dislocation or subluxation of the TMJ who were treated with the single injection technique prolotherapy with 25 % dextrose into the pericapsular tissues along with auriculotemporal nerve block and found encouraging results. RESULTS: Overall success rate in our study was 91.3 % (21/23) with a minimum follow up period of 13.9 months. Number of successfully treated patients requiring one injection was 7 (30.4 %), two injections was 8 (34.7 %) and requiring three injections was 6 (26.1 %). There were no permanent complications. CONCLUSION: Hence the use of 25 % dextrose as a proliferant to treat hypermobilty disorders of the TMJ is recommended by us as a first line treatment option as it is safe, economical and an easy procedure associated with minimal morbidity.

An in vitro study of the cytogenetic and cytotoxic effects of imatinib mesylate, STI571 on murine erythroleukemia GM-86 cells.

Imatinib mesylate, STI571, is a novel anticancer drug used to treat Philadelphia chromosome positive (Ph+) chronic myeloid leukemia. Studies have demonstrated the efficacy of imatinib mesylate in human cancers; however, its effects in murine cancer cell lines are not well documented. This study investigated the cytogenetic and cytotoxic effects of imatinib mesylate in vitro on virus-induced mouse erythroleukemia GM-86 cells. Cytogenetic studies revealed a noticeable increase in chromosomal abnormalities and multinucleation, as well as micro and macronuclei formation in treated cells. An increase in abnormalities such as condensed nuclei and nuclear and cytoplasmic degradations were also detected in cells treated with imatinib mesylate. It is suggested that the reduction in cell proliferation, mitotic index, and increase in cell damaging effects observed in imatinib mesylate-treated GM-86 cells were a result of the induced chromosomal and nuclear abnormalities.

Failure to detect chromosome damage in vivo in Friend virus-infected leukemic mice.

The cytogenetic activity of Friend virus (FV) was tested in vivo on spleen and bone marrow cells of FV-infected leukemic C3H/HeJ and STS mice. No specific chromosome rearrangements were detected in the infected animals. Some chromosome abnormalities were recorded in both normal and diseased animals; however, aberrations did not significantly increase in the leukemic groups.

Repair of cleft lip on relatively older children with anthropometrical surgical outcome.

A prospective study was done on 54 patients aged over 6 months with cleft lip with or without cleft palate admitted in the department of pediatric surgery of Mymensingh Medical College Hospital during the period from Oct 2002 to Dec 2004. The anthropometrical surgical outcome was evaluated by measuring the length, diameter and thickness of hemilip and diameter of nostril both pre and postoperatively (according to schedule). Patients were categorized into three groups according to their age. Mean Corrective rate was evaluated and it was shown 95% in the 1(st) age group, 93% in 2(nd) age group and 95.55% in the 3(rd) group. Complication was evaluated in only 16.66% of patients. Regarding the out come scar, cupid's bow, notching, labial and nasal symmetry were taken in consideration. Beside these this study might play a comparative role with the results of correction of cleft lip in early age.

Response of Mouse Breast Cancer Cells to Anastrozole, Tamoxifen, and the Combination.

The murine breast cancer cells (4T1) grown both in female BALB/c mice and in culture were treated with anastrozole (50 $\mu$ g/mL), tamoxifen citrate (5 $\mu$ g/mL), and the combination of the two drugs in order to determine treatment efficacies, toxic potential, and the mechanism of cell death. The in vivo treatments were evaluated by monitoring tumor growth, development, and life span. The in vitro effects were measured through cell growth kinetics, cell proliferation, mitochondrial membrane potential disruption assay, and light and scanning electron microscopy. All drug treatments extended the mean life span of the 4T1-inoculated tumor-bearing mice; however, only tamoxifen and combination treatments statistically increased the life span when compared to untreated mice. Although the most drug inhibitory effect on cell multiplication was observed in the combination treatment, both anastrozole and tamoxifen individually inhibited cell proliferation significantly at most time periods in this mouse breast cancer cell line. The mitochondrial membrane potential disruption assay demonstrated significant increase in the percent of cells undergoing apoptosis in all treatment groups. However, the combination treatment was the most effective in inducing cell death via apoptosis. Light and scanning electron microscopy of the treated cells revealed characteristics such as rounding, clumping, and shrinkage of the cells as well as formation of cell surface blebbing and apoptotic bodies suggestive of cell death via apoptotic pathway.

In Vitro Investigations on the Toxicity and Cell Death Induced by Tamoxifen on Two Non-Breast Cancer Cell Types.

Tamoxifen, a potent anticancer agent known to interrupt the enhanced estrogen activity of malignant mammary gland cells, was recently approved by the Food and Drug Administration (FDA)for the treatment of breast cancer. In this investigation, the toxic effects of tamoxifen were evaluated through cell multiplication, and cytological, surface ultrastructural, and biochemical studies on human cervical carcinoma cells (HeLa)and/or murine erythroleukemic (MEL) cells (BB-88). Tamoxifen treatment demonstrated an inhibitory effect on HeLa cell multiplication at lower concentrations and toxicity at higher concentrations and longer treatment durations. The drug also triggered morphological and biochemical changes as revealed by light microscopy, scanning electron microscopy (SEM), fluorescence microscopy, Nucleosome ELISA, and the DNA smear pattern. Cytological observations showed nuclear condensation, cell shrinkage, multinucleation, and apoptotic bodies. Surface ultrastructure of tamoxifen treated cells examined under the SEM revealed abnormalities such as membrane blebbing, holes, and cytoplasmic extrusions, all of which are characteristics of programmed cell death (apoptosis). Redistribution of the membrane phospholipid phosphatidylserine (PS) from the protoplasmic surface of the plasma membrane to the cell surface was identified using annexin V-enhanced green fluorescent protein (EGFP) in tamoxifen treated MEL BB-88 cells, a general feature of cells undergoing apoptosis. Tamoxifen treated cells demonstrated internucleosomal damages of the genomic DNA and DNA fragmentations, evidenced by an increase in free nucleosomes, and distinctive DNA smear patterns on the agarose gel.

Genotoxic effects of gossypol acetic acid on cultured murine erythroleukemia cells.

Gossypol acetic acid, a male anti-fertility drug, was evaluated for its effects on cell multiplication, chromosomes, scheduled and unscheduled DNA synthesis, and the surface ultrastructure in cultured murine erythroleukemia cells (clone 6A11A). Gossypol treatments inhibited cell multiplication at 10 and 20 micrograms/ml concentrations and this inhibitory effect increased with elevated dosage and prolonged treatment. Gossypol significantly depressed the mitotic index but did not alter chromosome numbers or increase the frequency of chromosomal structural abnormalities. Cell fraction techniques revealed that gossypol induced a negative effect on cellular DNA synthesis at concentrations as low as 3.3 micrograms/ml after 24 hr of treatment. The number of cells undergoing DNA synthesis decreased with increasing dosages and durations of drug exposure. An unscheduled DNA synthesis assay (UDS) found gossypol to be an active UDS-inducing agent at certain dose levels and treatment times, as measured by increase in net nuclear gain and percentage of UDS cells (ANOVA, Bonferroni test, P less than 0.05). A scanning electron microscope study revealed that 10 micrograms/ml treatment with gossypol caused changes in mouse erythroleukemia cell surface ultrastructure characterized by general balding and the appearance of holes, often after 48 hr of treatment.

The effect of chlormethiazole on serum gonadotrophins and testosterone in chronic alcoholics.

Serum gonadotrophins (LH and FSH) and testosterone concentrations were estimated by radioimmunoassay in 7 male chronic alcoholics on admission and following treatment with chlormethiazole for 6 days. Individual and mean values of serum LH and FSH were within normal limits both before and after treatment, but serum testosterone concentrations were found to be slightly higher than normal on both occasions. Chlormethiazole does not seem to have any effect on serum gonadotrophins or testosterone. It is further suggested that chlormethiazole does not interfere with the hypothalamic releasing factors for pituitary gonadotrophins and that it has no direct effect on testicular endocrine functions.

Chlormethiazole: current status in the treatment of the acute ethanol withdrawal syndrome.

Comparative clinical studies of Chlormethiazole with a vast array of pharmacologically unrelated drugs like benzodiazepines, tiapride, bromocriptine, carbamazepine and phenothiazines over the years clearly established it as a useful, dependable and effective drug to treat patients with moderate to severe ethanol withdrawal syndrome, when used early in a flexible reducing regime tailed off over 7-10 days. It has been found to be highly effective in the treatment, and particularly in the prevention of DT's in high-risk patients, if given at an early stage. This paper critically reviews the important international clinical trial literature of various drugs currently used in the treatment of ethanol withdrawal syndrome, including DT's, it highlights the efficacy and superiority of Chlormethiazole over other drugs, and also discusses the probable mechanism of its actions in these conditions.

Relationship between hepatic histology and conventional biochemical liver function test in chronic alcoholic patients.

This paper explores the relationship between hepatic histology and conventional biochemical liver function tests in 125 chronic alcoholic patients. On the basis of the results obtained, it is suggested that abnormal biochemical liver function tests may offer important clues for further invasive investigations to establish the diagnosis of alcoholic liver disease.

The dexamethasone suppression test in chronic alcoholics with and without depression and its relationship to their hepatic status.

Fifty consecutively admitted male alcoholics (mean age = 42.8 +/- 8.5 years) were selected. This study shows objectively that 31/50 chronic alcoholics (62%) were found to be severely depressed (Hamilton Depression Rating Scale (HRS) greater than 22); 12/50 (24%) moderately depressed (HRS = 16-22); and 7/50 (14%) were not depressed (HRS less than 15). According to dexamethasone suppression test (DST) results, 8 out of 50 patients showed escape from suppression with 2 mg dexamethasone while 42/50 showed normal suppression. Depression in alcoholics may be of neurotic type or it may be ethanol-induced reactive depression. Raised cortisol levels and abnormal DST response showed a definite tendency towards normalisation after total abstinence accompanied by clinical improvement of depressive symptomatology. The DST showed improvement on improvement of mood and sleep in these patients during total abstinence. An abnormal DST response in chronic alcoholics seems to be state-related and not trait-dependent; it seems to be a non-specific test for depression in alcoholics. Hepatic status was affected equally in both suppressors and non-suppressors of DST. It is therefore suggested that abnormal DST in alcoholics may be due to the abnormality of the hypothalamo-pituitary-adrenocortical (HPA) axis and not due to abnormal hepatic function or histological status.

Relationship between plasma adrenocorticotrophic hormone and cortisol concentrations in chronic alcoholic patients with depression.

In 20 hospitalized male chronic alcoholic patients, plasma adrenocorticotrophic hormone (ACTH) levels were estimated by radioimmunoassay and cortisol levels by the competitive protein binding (CPB) method with radioactive selenium-75 on admission and during abstinence along with rating of the degree of depression immediately after the acute phase of the ethanol withdrawal syndrome was over. Duration of drinking ranged from 5 to 25 years and average daily ethanol intake was between 100 and 150 g. Plasma ACTH levels were found to be raised in drinking chronic alcoholics. There was a positive and statistically significant correlation between depression ratings and plasma ACTH concentrations (r = + 0.379; P less than 0.05). In chronic alcoholism the negative feedback mechanism seems to be disturbed between plasma ACTH and cortisol levels which are not normalised after 1 week of total abstinence. Chronic ethanol ingestion might have a direct stimulatory effect on the adrenal cortex leading to dysregulation of the hypothalamo-pituitary-adrenocortical axis.

Relationship between plasma cortisol concentrations and depression in chronic alcoholic patients.

Plasma cortisol levels were estimated by the competitive protein binding (CPB) method with radioactive selenium-75 in 32 male chronic alcoholics with depression. The degree of depression was rated by the Hamilton Depression Rating Scale (HDRS). Duration of drinking ranged from 5-25 years with an average daily amount of ethanol intake of 100-150 g (equivalent to half a bottle of spirits). Plasma cortisol levels were often raised in drinking chronic alcoholics and there was a strongly positive and statistically highly significant correlation between them and depression ratings (r = +0.56; P = 0.001). It is possible that the diurnal rhythm of cortisol secretion is disturbed or adreno-cortical activity is stimulated in these patients due to chronic ethanol ingestion. It is further suggested that brain serotonin deficiency known to occur in chronic alcoholics might lead to raised plasma cortisol levels in ethanol-induced depression.

Thyroid status in chronic alcoholics.

Serum thyroxine (T4), triiodothyronine (T3) and thyrotrophin (TSH) were measured by radioimmunoassay in 39 chronic alcoholics on admission. Two patients had a reduced circulating serum T4 and eight showed a low serum T3 level but basal TSH was not raised in any of the 39 patients. Interestingly, low T4 and T3 levels returned to normal after abstinence and high protein and vitamin supplemented diet for one week. It is clear from our observations that a normo- or hypo- rather than a hypermetabolic or hyperthyroid state is more common in drinking chronic alcoholics. Ethanol-induced "low T3 syndrome" has also been described and a mechanism of its pathogenesis is suggested.

Plasma vitamin E status in chronic alcoholic patients.

Plasma vitamin E (alpha-tocopherol) concentrations were estimated by high performance liquid chromatography (HPLC) in 50 consecutively admitted chronic alcoholics (M = 44;F = 6;mean age +/- S.D. = 42.94 +/- 10.97;age range = 28-70 years) on admission and in 25 of them it was repeated during abstinence (6th day) while undergoing conventional detoxification therapy with polyvitamins (except vitamin E) and hypno-sedative drugs. Thirty percent of the patients were found to be deficient on admission and while on routine hospital diet during therapy, 20% of the patients were still deficient. It is, therefore, suggested that chronic alcoholics should be treated routinely with vitamin E along with other polyvitamins during detoxification in alcoholic units.

Plasma urea and creatinine status in chronic alcoholics.

Plasma urea and creatinine concentrations were estimated by Auto-Analyzer in 128 chronic alcoholics (103 males, 25 females; mean age +/- SD = 42.73 +/- 6.53; age range 20-60 years). Plasma levels of both urea (mean +/- SD = 3.46 +/- 1.31; normal range 2.0-6.5 mmol/l) and creatinine (mean +/- SD = 87.86 +/- 15.45; normal range 60-120 mumol/l) were found to be within normal limits. It is concluded from our observations that chronic ethanol ingestion per se is not nephrotoxic. The kidney seems to be the only vital organ generally spared in chronic alcoholics without advanced alcoholic liver disease or hepato-renal syndrome.

The effect of Naftidrofuryl on ethanol-induced liver damage in chronic alcoholic patients.

A prospective double-blind placebo-controlled trial of intramuscular Naftidrofuryl was carried out on 32 randomly selected hospitalized male alcoholic patients with clinical, biochemical and histological evidence of hepatic damage. Seventeen patients received the drug (40 mg in 5 ml i.m. three times daily for 6 days) and 15 patients received a placebo (5 ml in normal saline i.m. three times daily for 6 days). The drug was well tolerated and there were no adverse side-effects. Naftidrofuryl significantly improved the physiological function of the liver cells as reflected by indocyanine green (ICG) clearance by the liver (t = 2.61; p less than or equal to 0.02) and also caused a larger fall in raised serum levels of gamma glutamyl transpeptidase (GGT) than did the placebo injections. Overall clinical improvement (e.g. appetite, body weight, reduced liver size, general sense of well-being) was more clearly evident in patients of the treated group than in those of the placebo group. Naftidrofuryl, therefore, appears to be of benefit in ethanol-induced liver damage and more extensive long-term trials are suggested in patients with alcoholic liver disease (ALD).