Rhino-orbito-cerebral mucormycosis: patient characteristics in pre-COVID-19 and COVID-19 period.

BACKGROUND: Rhino-orbito-cerebral-mucormycosis (ROCM), a rare and potentially fatal disease was seen in increasing numbers during the COVID-19 pandemic. This study describes and compares the patient characteristics and outcomes in COVID-19 associated mucormycosis (CAM) and non-COVID-19 mucormycosis (non-CAM). METHODOLOGY: CAM patients (24 cases) were recruited from the COVID-19 period and non-CAM (24 controls) from the pre-COVID-19 period. Clinical data of the CAM group was collected retrospectively with 3 month outcomes prospectively. The non-CAM group data was collected retrospectively. Patient characteristics were compared and risk factors for mortality in ROCM were assessed. RESULTS: Orbital symptoms [altered vision, restricted eye movements, ptosis] and intracranial involvement were higher in CAM patients on presentation. Similarly, the radiological involvement of orbit (orbital apex, superior orbital fissure) and intracranial cavity (intracranial thrombosis, cavernous sinus) was also higher in CAM patients. Newly detected diabetes was found only in CAM patients (29.2%). Although univariate analysis suggested an increased mortality risk in ROCM patients with orbital involvement, the multivariate analysis showed no increased risk with any of the parameters assessed, including COVID-19 positivity. CONCLUSIONS: Compared to the non-CAM, the disease presentation was severe in CAM with higher frequency of orbital and intracranial involvement. However, with early detection and treatment, the short term survival was comparable in both groups.

A prospective randomized controlled trial comparing early postoperative complications in patients undergoing loop colostomy with and without a stoma rod.

AIM: A stoma rod or bridge has been traditionally placed under the bowel loop while constructing a loop colostomy. This is believed to prevent stomal retraction and provide better faecal diversion. However, the rod can cause complications such as mucosal congestion, oedema and necrosis. This single-centre prospective randomized controlled trial compared outcomes after creation of loop colostomy with and without a supporting stoma rod. The primary outcome studied was stoma retraction rate; other stoma-related complications were studied as secondary outcomes. METHOD: One hundred and fifty-one patients were randomly allotted to one of two arms, colostomy with or without a supporting rod. Postoperative complications such as retraction, mucocutaneous separation, congestion and re-exploration for stoma-related complications were recorded. RESULTS: There was no difference in the stoma retraction rate between the two arms (8.1% in the rod arm and 6.6% in the no-rod arm; P = 0.719). Stomal necrosis (10.7% vs 1.3%; P = 0.018), oedema (23% vs 3.9%; P = 0.001), congestion (20.3% vs 2.6%; P = 0.001) and re-admission rates (8.5% vs 0%; P = 0.027) were significantly increased in the arm randomized to the rod. CONCLUSION: The stoma rod does not prevent stomal retraction. However, complication rates are significantly higher when a stoma rod is used. Routine use of a stoma rod for construction of loop colostomy can be avoided.

Scrub typhus meningitis: An under-recognized cause of aseptic meningitis in India.

BACKGROUND: Central nervous system (CNS) involvement in scrub typhus is seen in up to a quarter of patients. However, the literature on cerebrospinal fluid (CSF) analysis and outcome in meningitis/meningo-encephalitis due to scrub typhus is scant. MATERIALS AND METHODS: This retrospective study included patients who were admitted to a medical college hospital with scrub typhus meningitis/meningo-encephalitis between 2005 and 2011. The clinical and laboratory profile, details of CSF analysis and outcome were documented. RESULTS: The study included 189 patients with meningitis/meningo-encephalitis due to scrub typhus. The mean age of the patients was 41 ± 4 years. The mean duration of fever before presentation was 9.4 ± 3 days. The common presenting complaints were headache (64.2%), nausea/vomiting (60%), altered sensorium (53.7%) and seizures (22.1%). The presence of an eschar was documented in 27.5% of the patients. The mean CSF white blood count was 80 cells/cu mm (range: 5-740). There was a clear lymphocyte predominance (mean 87.6%). The mean CSF protein level was 105 mg% (range: 13-640). The mean CSF sugar level was 63.9 mg% (range 25-350), and was less than 40 mg% in 11.1% of the cases. The case fatality rate was 5.8% (11/189). Univariate analysis showed the presence of an eschar (15.4% vs 2.2%; Odds Ratio [OR]: 8.1) and altered sensorium (9.8% vs 1.1%; OR: 9.2) to be significant predictors of mortality. CONCLUSIONS: In endemic regions, scrub typhus should be considered in the differential diagnosis of aseptic meningitis. Modest elevation of cells in the CSF with lymphocytic pleocytosis and multi-organ involvement may indicate scrub typhus meningitis/meningo-encephalitis.

Acute infectious purpura fulminans due to probable spotted fever.

Purpura fulminans (PF) is associated with several infections, most notably with meningococcus, staphylococcus, and streptococcus infections. However, there are few reports of association of this entity with spotted fever from India. We report the case of a 55-year-old man who presented with fever, headache, and myalgia. On the seventh day of fever he developed nonblanching purple hemorrhagic purpura on the trunk and most prominently on the extremities consistent with purpura fulminans. Immunofluorescent assay confirmed the diagnosis of spotted fever. PF though common with rocky mountain spotted fever (RMSF) is rarely seen in association with Indian tick typhus, the usual cause of spotted fever in India.

Eschar in scrub typhus: a valuable clue to the diagnosis.

BACKGROUND: Scrub typhus is an acute febrile illness widely prevalent in the 'tsutsugamushi triangle' region of the world. Clinical features include fever, myalgia, headache, rash, and a pathognomonic eschar. An eschar is formed by the bite of chigger mite that inoculates the causative agent of Scrub typhus Orientia tsutsugamushi. The aim of this study is to determine the most common sites of eschars over the bodies of patients with Scrub typhus. MATERIALS AND METHODS: In a retrospective analysis, we examined a total of 418 patients who presented to Christian Medical College, Vellore between 2009 and 2012 with an acute febrile illness and an eschar on clinical examination and confirmed to have scrub typhus with a positive Scrub typhus IgM ELISA test. We studied the distribution of eschars over the bodies of 418 patients with Scrub typhus. RESULTS: There was a significant difference in the distribution of eschars between males and females with a preponderance of the chest and abdomen (42.3%) among females and the axilla, groin and genitalia (55.8%) in males. Some unusual sites of an eschar were the cheek, ear lobe and dorsum of the feet. CONCLUSION: The eschar is the most useful diagnostic clue in patients with acute febrile illness in areas endemic for Scrub typhus and therefore should be thoroughly examined for its presence especially over the covered areas such as the groin, genitalia, infra-mammary area and axilla.

Cases of human fascioliasis in India: tip of the iceberg.

This report presents two cases of human fascioliasis from different states in India. Although only few cases of human fascioliasis have been reported from India previously, both these cases were encountered within a span of three months at this tertiary care centre. Case 1 had significant symptoms with episodes of fever, abdominal pain and eosiniphilia and underwent multiple diagnostic procedures before the correct diagnosis was reached. Case 2, who had few symptoms, had fascioliasis diagnosed with minimal evaluation. These different presentations seen at two ends of the clinical spectrum of disease along with findings of peripheral eosinophilia, and radiological findings led to a presumptive diagnosis that was then confirmed by microscopic examination of bile. Morphometric analysis of ova from these cases was suggestive of infestation with F. gigantica or a F. gigantica-like hybrid. Both patients were treated with triclabendazole which was imported from Geneva. The need to be aware of the possibility of occurrence of this disease and the inclusion of drugs used for treating the disease, in the Indian drug list, should be emphasized.

Xpert Ultra in diagnosing extrapulmonary TB: accuracy and trace calls.

INTRODUCTION: Xpert Ultra (Ultra) was developed to improve the detection of TB; however, data on Ultra´s diagnostic accuracy in extrapulmonary TB (EPTB) are limited.METHODS: In this prospective diagnostic accuracy study, 242 EPTB samples were subjected to Ultra and Xpert MTB/Rif (Xpert) testing, and these were compared with both culture and a composite gold standard.RESULTS: Compared to culture, Ultra sensitivity and specificity using bone, cerebrospinal fluid (CSF), lymph node and tissue samples, and overall were respectively 100% and 77.3%, 75% and 100%, 87.5% and 87.5%, 100% and 87%, and 89.7% and 87.4%; in comparison to the composite gold standard, Ultra´s sensitivity and specificity were respectively 66.7% and 100%, 17.6% and 100%, 46.9% and 95.7%, 38.5% and 94.1%, and 46.2% and 96.9%. Using latent class analysis, sensitivity and specificity were respectively 94.5% and 96.3% for Ultra, 65.5% and 99.8% for Xpert, and 58.6% and 99.2% for culture. There were 22/242 (9%) trace calls on Ultra.CONCLUSION: We found improved sensitivity for Ultra compared to Xpert, although Ultra specificity was lower, with a large number of trace results (9%).

India's National Action Plan on Antimicrobial Resistance: a critical perspective.

Antimicrobial resistance (AMR) is widely recognised as a global health threat, which is projected to account for more deaths than cancer by 2050. The Government of India has formulated a National Action Plan to tackle AMR (NAP-AMR), largely modelled on the World Health Organization's Global Action Plan on AMR. While the NAP-AMR successfully mirrors the Global Action Plan and lays out ambitious goals, we find that the lack of financial allocation across states, poor enforcement and inadequate multisectoral co-ordination have hampered progress. A broader focus on improving infrastructure for water and sanitation, linking the issue of AMR to existing vertical health programmes for human immunodeficiency virus (HIV) and tuberculosis (TB), prioritising infection prevention and control, strengthening the frontline healthcare workforce in rural and peri-urban settings to reduce reliance on antibiotics, leveraging point-of-care testing and mobile app-based health interventions for diagnosis and surveillance, and adopting a socioecological approach to health and development would help to create an enabling environment for concrete action on AMR in India.

Clinical use of ictal SPECT in secondarily generalized tonic-clonic seizures.

Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic-clonic seizures obtained during epilepsy surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization. This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures can help localize the region of seizure onset.

Cortical and subcortical networks in human secondarily generalized tonic-clonic seizures.

Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

BRCA1 regulation on ß-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer.

Human chorionic gonadotropin ß (ß-hCG) has been implicated in breast tumorigenesis. However, the role of this hormone is highly controversial as certain studies suggest it has anti-tumor properties while others have found it to be pro-tumorigenic. To unveil the truth, we have analyzed the expression of ß-hCG in breast cancer. We identified for the first time that ß-hCG expression is linked to BRCA1 status and its overexpression is seen in BRCA1 mutated breast cancer cells, BRCA1 conditional knockout mouse breast cancer tissues and BRCA1 floxed basal cell carcinoma (BCC) tissues. An analysis of three large, transcriptomic data sets from TCGA (The Cancer Genome Atlas) expression profile confirmed the inverse correlation between BRCA1 and ß-hCG in human breast cancer. Using ChIP and luciferase assays, we also demonstrated that the cancer cells with wild-type but not mutant BRCA1 directly repress the expression of ß-hCG by binding to its promoter. Further, ß-hCG promotes migration and invasion predominantly in BRCA1 mutant breast cancer cells. Interestingly, stable overexpression of ß-hCG in BRCA1 mutant but not wild-type breast cancer cells results in the formation of spheres even on monolayer cultures. The cells of these spheres show high expression of both EMT and stem cell markers. Since ß-hCG belongs to a cysteine knot family of proteins like TGFß and TGFß signaling is deregulated in BRCA1 defective tumors, we checked whether ß-hCG can mediate signaling through TGFßRII in BRCA1 mutated cells. We found for the first time that ß-hCG can bind and phosphorylate TGFßRII, irrespective of LHCGR status and induce proliferation in BRCA1 defective cells. Our results confirmed that there exists a transcriptional regulation of BRCA1 on ß-hCG and BRCA1 mutation promotes ß-hCG mediated tumorigenesis through TGFßRII signaling. Thus inhibiting ß-hCG-TGFßRII could prove an effective treatment strategy for BRCA1 mutated tumors.

Predictors of multi-organ dysfunction in heatstroke.

BACKGROUND: Heatstroke is a medical emergency that results from failure of thermoregulatory mechanism coupled with an exaggerated acute phase response, causing an elevation in core body temperature that rises above 40 degrees C, producing multi-organ dysfunction. It carries a high mortality rate, and in survivors, a risk of permanent neurological damage. OBJECTIVE: To investigate predictors of multiple organ dysfunction syndrome in patients presenting with heatstroke. METHODS: We investigated 28 patients admitted to a hospital in southern India during the period January 1998 to December 2001. Using a standard form, we collected data on the patients' characteristics, laboratory data, and outcome, and compared those with multiple organ dysfunction with those without such dysfunction. RESULTS: We found that more than three quarters of the studied patients developed multiple organ dysfunction, with the most common dysfunction being respiratory failure. Among the selected predictors, metabolic acidosis 14 of 16 patients, 87.5%; p = 0.011, elevated CPK 17 of 19 patients, 89.5%; p = 0.005, and liver enzymes elevated more than twice the normal (11 of 18 patients, 61%; p = 0.02) had the highest correlation with dysfunction of two or more organs. CONCLUSIONS: The high mortality observed in heatstroke is secondary to multi-organ dysfunction, and among the various parameters assessed, high levels of CPK (>1000 IU/l), metabolic acidosis, and elevated liver enzymes are predictive. Aggressive measures to lower the body temperature with other supportive therapy could substantially reduce the mortality.

Resistance of the dopamine D2L receptor to desensitization accompanies the up-regulation of receptors on to the surface of Sf9 cells.

Dopamine D2 receptor agonists are commonly used in the control of PRL-secreting adenomas, and the sensitivity of dopamine agonists during long term therapy is exquisite. However, the molecular mechanisms responsible for the maintenance of this cellular sensitivity to dopamine agonists remain poorly understood. In the present study, we examined the agonist-induced regulation of the human D2L receptor expressed to a specific activity of approximately 1 pmol receptor/mg protein in Sf9 insect cells. Treatment of D2L receptor-expressing cells with dopamine for up to 3 h resulted in no detectable change in the ligand-binding properties of the receptor and a approximately 120-fold reduction in the potency, but not the efficacy, of D2L receptors to mediate dopamine inhibition of forskolin-stimulated adenylyl cyclase activity. This resistance of the D2L receptor to agonist-induced desensitization was accompanied by a approximately 28% translocation of intracellular D2L receptors to the cell surface, as quantified by cellular fractionation and radioligand binding and visualized by whole cell immunocytochemical staining and confocal microscopy. Immunoblot analysis of the P2 membrane fraction revealed that surface D2L receptors comprised monomers and dimers. Treatment of D2L receptor-expressing cells with the protein synthesis inhibitor cycloheximide significantly reduced the basal expression level of receptors, but did not block the agonist-induced up-regulation of receptors. Longer periods of dopamine exposure for 24 h brought about a small increase in surface receptor density. However, when these studies were conducted in the presence of cycloheximide, receptor density was marginally reduced, suggesting that receptor synthesis accounts for the maintenance of cellular receptor density under these conditions. We conclude that the resistance of the D2L receptor-coupled adenylyl cyclase system to agonist-induced desensitization is attributed to the up-regulation of surface receptors after the translocation of existing intracellular receptors and de novo receptor synthesis.

Oligomerization of dopamine and serotonin receptors.

Until recently, it has largely been assumed that G protein-coupled receptors (GPCRs) function as monomeric entities. However, over the past few years, we and others have documented that GPCRs can form dimers and oligomers, leading to a re-evaluation of the mechanisms thought to mediate GPCR function. Despite the growing number of investigations into dimerization, little is known about the structural basis of receptor-receptor interactions and the functional consequences of dimer formation. Here, we present a brief review of some insights we have gained into the dimerization of dopamine and serotonin receptors. We have demonstrated that agonist-regulated trafficking is identical for receptor monomers and dimers, however, agonist treatment appears to stabilise the receptor oligomers. An investigation of the structural assembly between receptors involved in dimerization showed that there are several sites of interaction including hydrophobic transmembrane domain interactions and intermolecular disulphide bonds. We have also examined receptor hetero-oligomerization and demonstrated the potential for novel functions as a result of these associations. Finally, as a result of these observations, we have been able to present evidence that GPCRs function as oligomers in the cell.

Effect of propylthiouracil treatment on NADPH-cytochrome P450 reductase levels, oxygen consumption and hydroxyl radical formation in liver microsomes from rats fed ethanol or acetone chronically.

The antithyroid drug propylthiouracil (PTU) has been shown previously to reduce hepatic oxygen utilization and to protect the liver from ethanol-induced injury. The present study examined the effect of PTU on hepatic microsomal oxygen consumption and on the activities of NADPH-cytochrome P450 reductase (CYP-reductase) and cytochrome P4502E1 (CYP2E1) in rats receiving ethanol or acetone chronically. Liver microsomes from rats treated with ethanol for 29 days displayed increases in (i) O2 consumption (70%), (ii) hydroxyl radical (.OH) production (49%) and (iii) ethanol oxidation (50%). Microsomal CYP2E1 levels were increased markedly by chronic ethanol administration, while CYP-reductase was affected marginally, but not significantly (P = 0.06). Chronic treatment with acetone for 14 days, produced similar effects, except that .OH production was not enhanced. Administration of PTU (25 mg/kg/day) to ethanol- or acetone-fed rats, for 10 and 14 days, respectively, led to a marked reduction in the levels and activity of CYP-reductase, and to a decrease in the rates of microsomal O2 consumption, .OH production and ethanol oxidation, but did not lower the levels of CYP2E1 or the metabolism of the CYP2E1 substrate N,N-nitrosodimethylamine. These data suggest that the ability of PTU to protect the liver from ethanol-induced injury may be due to a reduction in the levels of CYP-reductase, thereby minimizing the enhancement of microsomal oxygen consumption and free radical generation associated with ethanol-induced CYP2E1 activity.

Emergence of multidrug-resistant Salmonella typhi in rural southern India.

Multidrug-resistant Salmonella typhi has spread to many parts of India, causing severe therapeutic problems. Of the 305 clinically suspected cases of enteric fever seen at Kasturba Hospital in Manipal, Karnataka between January 1990 and June 1991, Salmonella bacteremia was detected in 134 patients; 102 of these were caused by S. typhi. Eighty (78.4%) of the isolates from S. typhi-infected patients were resistant to conventional antibiotics used in the treatment of typhoid fever (i.e., ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole). No in vitro resistance was observed to ciprofloxacin, norfloxacin, and gentamicin. Major complications were seen in four patients infected by multiresistant S. typhi; three responded well to ciprofloxacin. The fourth patient died of hemorrhage and acute renal failure, even after receiving ciprofloxacin. In addition, less severe complications such as hepatitis and jaundice were observed in 12 other patients. Seventy-six of the multiresistant S. typhi belonged to phage type O biotype II and four were of untypeable Vi strains. The emergence of multidrug-resistant S. typhi has necessitated the use of fluoroquinolones in the therapy for enteric fever.

Tuberculosis in health service employees in Northern Ireland.

Tuberculosis can be transmitted from patients to health care workers. However, where the incidence of tuberculosis is low, and good infection control practices exist, the risk of health care workers acquiring the disease is likely to be small. The objective of this study was to determine the rate of notification of tuberculosis in health care workers in Northern Ireland compared with the general population. Information from the statutory tuberculosis notification forms for the period 1982-1991 was entered on to a computer database. Those patients involved in health care occupations were identified and age and sex standardized incidence rates were calculated. The overall notification rate for tuberculosis was 7.4 cases per 100,000 of general population. There was no significant increase in notification of tuberculosis among health care workers [standardized incidence ratio: 126% (95% CI 91-170)]. No cases were diagnosed as a result of screening methods performed during employment. It was concluded that health care workers in Northern Ireland did not have a significantly increased incidence of tuberculosis compared with the general population over the 10-year period studied. This suggests that the risk of transmission from patients to health care workers is negligible in the setting of a low general incidence of tuberculosis and good infection control practice. Under these circumstances, the present findings support the cessation of routine screening of health care workers.

Inhaled steroids in patients with bronchiectasis.

The effect of inhaled beclomethasone diproprionate (1500 micrograms day-1) on symptoms, pulmonary function and sputum production was examined in a double-blind, placebo-controlled, cross-over study in 20 patients with bronchiectasis. An 18% reduction in daily sputum production (P less than 0.003) was observed on treatment with inhaled steroid compared to placebo. A small, significant, improvement in morning peak expiratory flow rate (P less than 0.03) and forced expiratory volume in 1 s (P less than 0.03) was seen but the absolute changes are unlikely to be of clinical importance. Symptom scores for cough improved significantly (P less than 0.02). Inhaled steroids may have a role in the management of bronchiectasis by reducing cough and sputum production.