A metabolic perspective on nitric oxide function in melanoma.

Nitric oxide (NO) generated from nitric oxide synthase (NOS) exerts a dichotomous effect in melanoma, suppressing or promoting tumor progression. This dichotomy is thought to depend on the intracellular NO concentration and the cell type in which it is generated. Due to its central role in the metabolism of multiple critical constituents involved in signaling and stress, it is crucial to explore NO's contribution to the metabolic dysfunction of melanoma. This review will discuss many known metabolites linked to NO production in melanoma. We discuss the synthesis of these metabolites, their role in biochemical pathways, and how they alter the biological processes observed in the melanoma tumor microenvironment. The metabolic pathways altered by NO and the corresponding metabolites reinforce its dual role in melanoma and support investigating this effect for potential avenues of therapeutic intervention.

Neuroborreliosis in India - A Diagnostic Challenge and a Great Mimicker: A Case Series.

OBJECTIVES: Neuroborreliosis is generally known to be a disease confined to the Western part of the globe. It is not commonly encountered in this part of the world. Interestingly, we recently came across a series of cases of Lyme's disease with a plethora of neurological presentations. Most of the cases were a diagnostic dilemma, with poor response to immunotherapy and on subsequent evaluation all were found to have positive Borrelia antibodies. MATERIALS AND METHODS: Eight cases were selected from the tertiary care hospital in North western India. Patients were suspected to have Neuroborreliosis whose neurological presentations were atypical for other classical neurological disorders, who had a progressive or relapsing clinical course and had responded poorly to the initial treatment given for the previous neurological diagnosis. Skin lesions were present in some cases. The patients underwent a detailed clinical assessment which comprised of an elaborate history including history of travel, any insect bite or skin rashes along with a complete systemic and neurological examination. All the required blood investigations, Magnetic Resonance Imaging (MRI) Brain, Computer Tomography Angiography (CT), Nerve conduction study (NCS) and Electromyographic (EMG) studies and Cerebrospinal fluid (CSF) studies were done as indicated in each case. Borrelia antibody titre was done in all the patients using immunoblot technique. RESULTS: Among the 8 patients, 6 were male and 2 were females. The age group was between 25-70 years. The clinical presentation was acute, subacute or chronic. One patient gave a clear history of tick bite. Two patients had skin lesions and one had the pathognomic "eschar". All the suspected 8 patients had either IgG or IgM or both IgG and IgM Borrelia antibodies positive. Almost all the patients had previously received either steroids or intravenous immunoglobulins, but had not adequately responded to immunotherapy. These patients were given a trial of injectable Ceftriaxone and oral Doxycycline. Most of them either showed partial or complete clinical improvement. CONCLUSION: Lyme's disease, a common disease of the west does exist in the Indian subcontinent as well. Because of increasing global travel and migration and change in vector habitat the disease seems to have percolated in the non endemic areas too. Proper history of travel or exposure to tick bite is important. We want to emphasize, Neuroborreliosis, a great mimicker may have diverse and varied neurological presentations and has a potential for reversibility with appropriate treatment even after a significant delay in diagnosis.

Evaluation of correlation between CD44, radiotherapy response, and survival rate in patients with advanced stage of head and neck squamous cell carcinoma (HNSCC).

PURPOSE: Cancer stem cells (CSCs) constitute a distinctive subpopulation of cancer cells that are competent in tumor initiation, invasion, recurrence, and resistance to chemoradiotherapy. CD44, a hyaluronic acid (HA) receptor has been considered as a potential CSC marker in head and neck cancer. The purpose of this study is to evaluate the correlation between CD44 and clinicopathological parameters, treatment response, survival, and recurrence. METHODS: The CD44 expression was examined by immunohistochemistry (IHC) in 90 samples of head and neck squamous cell carcinoma (HNSCC) confirmed patients. The expression of CD44 and its association with clinicopathological parameters, treatment response, and survival was determined. RESULTS: In all HNSCC patient samples, CD44 was expressed consistently at different intensities. Tumor size (p < 0.001), stage (p < 0.001), and treatment response (p < 0.001) showed statistically significant association with CD44 expression. Alcohol and CD44 were observed as independent predictors of response to radiotherapy using multivariate ordinal logistic regression analysis. Analysis of 2-year overall survival (OS) showed that CD44 expression (p = 0.02), tumor size (p = 0.001), lymph node status (p < 0.001), stage (p < 0.001), and grade (p = 0.007) were significantly associated with OS. Using Cox regression analysis, lymph node status (p = 0.001), grade (p < 0.001), recurrence (p < 0.001), and CD44 expression (p = 0.003) were found to be potential independent predictors of OS. CONCLUSION: Our findings suggest that CD44 contributes to resistance to radiotherapy and poor OS. The results also suggest that except for CD44 there could be other factors such as lymph node metastasis, grade, and alcohol which should be investigated as potential targets for therapy.

Association of ALDH1 with Response to Radiotherapy and Its Impact on Survival in Patients with Advanced Stage of Head and Neck Squamous Cell Carcinoma (HNSCC).

BACKGROUND: The presence of cancer stem-like cells within tumor microenvironment distinctly governs response to chemo-radiotherapy. The ALDH1 (Aldehyde dehydrogenase 1) has emerged as a cancer stem cell (CSC) marker in various tumors. The aim of the study was to examine the expression of ALDH1 in HNSCC patients undergoing radiotherapy to evaluate its correlation with clinicopathological parameter, treatment response and survival. METHODS: Expression of ALDH1 was evaluated by immunohistochemistry in 90 histopathologically confirmed HNSCC patients and 90 matched controls. The association between ALDH1 expression, clinicopathological parameters and treatment response was determined. RESULTS: The immunohistochemistry results showed that ALDH1 was consistently expressed in all the HNSCC specimens although at different intensities. On the other hand, control specimens did not show similar expression of ALDH1. ALDH1 expression demonstrated statistically significant association with tumor size (p<0.001), lymph node status (p<0.001), stage (p<0.001), grade (p<0.001) and treatment response (p<0.001). Multivariate ordinal logistic regression analysis indicated alcohol and ALDH1 as an independent predictor of responsiveness to radiotherapy in HNSCC patients. Multivariate Cox regression analysis indicated that lymph node status (p=0.020), grade (p=0.006) and recurrence (p=0.002) were potential independent predictors of overall survival. CONCLUSION: From previous studies, ALDH1 has been contemplated not only as a promising prognostic and diagnostic marker but also as a likely drug target. Our study gives new understanding regarding the association between ALDH1, cancer prognosis and radioresistance. Our findings suggest that ALDH1, lymph node status, grade and alcohol could be the viable targets for HNSCC and it also provides new prospects for radiotherapy sensitivity in HNSCC.

Direct physical interaction of active Ras with mSIN1 regulates mTORC2 signaling.

BACKGROUND: The mechanistic (or mammalian) target of rapamycin (mTOR), a Ser/Thr kinase, associates with different subunits forming two functionally distinct complexes, mTORC1 and mTORC2, regulating a diverse set of cellular functions in response to growth factors, cellular energy levels, and nutrients. The mechanisms regulating mTORC1 activity are well characterized; regulation of mTORC2 activity, however, remains obscure. While studies conducted in Dictyostelium suggest a possible role of Ras protein as a potential upstream regulator of mTORC2, definitive studies delineating the underlying molecular mechanisms, particularly in mammalian cells, are still lacking. METHODS: Protein levels were measured by Western blotting and kinase activity of mTORC2 was analyzed by in vitro kinase assay. In situ Proximity ligation assay (PLA) and co-immunoprecipitation assay was performed to detect protein-protein interaction. Protein localization was investigated by immunofluorescence and subcellular fractionation while cellular function of mTORC2 was assessed by assaying extent of cell migration and invasion. RESULTS: Here, we present experimental evidence in support of the role of Ras activation as an upstream regulatory switch governing mTORC2 signaling in mammalian cancer cells. We report that active Ras through its interaction with mSIN1 accounts for mTORC2 activation, while disruption of this interaction by genetic means or via peptide-based competitive hindrance, impedes mTORC2 signaling. CONCLUSIONS: Our study defines the regulatory role played by Ras during mTORC2 signaling in mammalian cells and highlights the importance of Ras-mSIN1 interaction in the assembly of functionally intact mTORC2.

M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis.

Oncostatin M (OSM), an inflammatory cytokine belonging to the interleukin-6 (IL-6) superfamily, plays a vital role in multitude of physiological and pathological processes. Its role in breast tumor progression and metastasis to distant organs is well documented. Recent reports implicate OSM in macrophage M2 polarization, a key pro-tumoral phenomenon. M2 polarization of macrophages is believed to promote tumor progression by potentiating metastasis and angiogenesis. In the current study, we delineated the mechanism underlying OSM induced macrophage M2 polarization. The findings revealed that OSM skews macrophages towards an M2 polarized phenotype via mTOR signaling complex 2 (mTORC2). mTORC2 relays signals through two effector kinases i.e. PKC-α and Akt. Our results indicated that mTORC2 mediated M2 polarization of macrophages is not dependent on PKC-α and is primarily affected via Akt, particularly Akt1. In vivo studies conducted on 4T1/BALB/c mouse orthotropic model of breast cancer further corroborated these observations wherein i.v. reintroduction of mTORC2 abrogated monocytes into orthotropic mouse model resulted in diminished acquisition of M2 specific attributes by tumor associated macrophages. Metastasis to distant organs like lung, liver and bone was reduced as evident by decrease in formation of focal metastatic lesions in mTORC2 abrogated monocytes mice. Our study pinpoints key role of mTORC2-Akt1 axis in OSM induced macrophage polarization and suggests for possible usage of Oncostatin-M blockade and/or selective mTORC2 inhibition as a potential anti-cancer strategy particularly with reference to metastasis of breast cancer to distant organs such as lung, liver and bone.

Prevalence, Demographic Profile, and Psychological Aspects of Epilepsy in North-Western India: A Community-Based Observational Study.

AIMS: This study was undertaken to determine the prevalence of active epilepsy, assess the sociodemographic profile, and psychological aspects of epilepsy in the Jaipur district of Rajasthan, India. METHODS: We conducted a community-based, cross-sectional observational study covering both rural (n = 165,660) and urban (n = 179,142) populations of Jaipur district using a house-to-house survey. An adapted, pre-designed World Health Organization screening questionnaire was used to identify the cases. Those confirmed by neurologists as true seizures were included in the study. Cases were classified as per the International League against Epilepsy recommendation. Global Mental Health Assessment Tool electronic questionnaire was used to analyze psychological aspects of cases. The caregivers of the patients participated in the knowledge, attitude, and practice (KAP) survey. RESULTS: A total of 380 patients (258 men, 122 women) were identified with active epilepsy. The estimated prevalence of active epilepsy was 1.1/1,000 population and 71% of cases belonged to low socioeconomic classes. Primary treatment gap was documented in 18.8% of cases in our study, 38% of cases were non-compliant to treatment with poorer compliance in those on pol-therapy, 76% had some psychiatric disorder, anxiety and depression being the commonest, and positive family history of epilepsy was found in 4.7%. KAP survey revealed that only 15% of the respondents believed that epilepsy is non-curable, 74% denied its infectious nature, 26% believed that epilepsy occurs due to past sins, and 81% said that they would not marry persons with epilepsy. CONCLUSION: A relatively low prevalence (1.1/1,000) of active epilepsy and a smaller primary treatment gap (18.8%) was found in our study population. Almost three-fourth of cases had an associated psychological problem, Though caregivers were aware of the nature of disease, majority would not prefer to marry a person suffering from epilepsy.

Anti-proliferative effect of novel primary cetyl alcohol derived sophorolipids against human cervical cancer cells HeLa.

Sophorolipids (SLs) are glycolipid biosurfactants that have been shown to display anticancer activity. In the present study, we report anti-proliferative studies on purified forms of novel SLs synthesized using cetyl alcohol as the substrate (referred as SLCA) and their anticancer mechanism in human cervical cancer cells. Antiproliferative effect of column purified SLCA fractions (A, B, C, D, E and F) was examined in panel of human cancer cell lines as well as primary cells. Among these fractions, SLCA B and C significantly inhibited the survival of HeLa and HCT 116 cells without affecting the viability of normal human umbilical vein endothelial cells (HUVEC). The two fractions were identified as cetyl alcohol sophorolipids with non-hydroxylated tail differing in the degree of acetylation on sophorose head group. At an IC50 concentration SLCA B (16.32 µg ml-1) and SLCA C (14.14 µg ml-1) blocked the cell cycle progression of HeLa cells at G1/S phase in time-dependent manner. Moreover, SLCA B and SLCA C induced apoptosis in HeLa cells through an increase in intracellular Ca2+ leading to depolarization of mitochondrial membrane potential and increase in the caspase-3, -8 and -9 activity. All these findings suggest that these SLCAs could be explored for their chemopreventive potential in cervical cancer.

Silk Fibroin-Sophorolipid Gelation: Deciphering the Underlying Mechanism.

Silk fibroin (SF) protein, produced by silkworm Bombyx mori, is a promising biomaterial, while sophorolipid (SL) is an amphiphilic functional biosurfactant synthesized by nonpathogenic yeast Candida bombicola. SL is a mixture of two forms, acidic (ASL) and lactonic (LSL), which when added to SF results in accelerated gelation of silk fibroin. LSL is known to have multiple biological functionalities and hence hydrogels of these green molecules have promising applications in the biomedical sector. In this work, SANS, NMR, and rheology are employed to examine the assembling properties of individual and mixed SLs and their interactions with SF to understand the mechanism that leads to rapid gelation. SANS and NMR studies show that ASL assembles to form charged micelles, while LSL forms micellar assemblies and aggregates of a mass fractal nature. ASL and LSL together form larger mixed micelles, all of which interact differently with SF. It is shown that preferential binding of LSL to SF causes rapid unfolding of the SF chain leading to the formation of intermolecular beta sheets, which trigger fast gelation. Based on the observations, a mechanism for gelation of SF in the presence of different sophorolipids is proposed.

Combination of Steven-Johnson syndrome and neuroleptic malignant syndrome following carbamazepine therapy: a rare occurrence.

Stevens-Johnson syndrome (SJS) is a severe, episodic, acute mucocutaneous reaction that is most often elicited by drugs and occasionally by infections. The drugs commonly implicated as the cause of SJS are anticonvulsants, sulfonamides, non-steroidal anti-inflammatory drugs and antibiotics. Carbamazepine (CBZ) has been commonly implicated in SJS. Neuroleptic malignant syndrome (NMS) is a rare, life-threatening but potentially treatable condition. Among the neuroleptics, haloperidol (parenteral) is implicated as a most common drug for NMS. Though rare, association of NMS with CBZ and association of NMS with toxic epidermal necrolysis (TEN) in a single patient after administration of neuroleptics has been reported in the literature before. However, a combination of NMS and SJS in a single patient after administration of CBZ has not been reported so far. We present a patient with seizure who developed SJS and NMS following administration of CBZ.

Combination of AIDP and pyramidal signs associated with antecedent hepatitis A infection: a rare (co)occurrence.

Guillain-Barré syndrome (GBS) is a postinfectious illness and commonly occurs in association with infective agents such as Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, HIV, shigella, clostridium, Haemophilus influenzae; occasionally with acute hepatitis B, C, E; and more rarely with hepatitis A, as documented in various case reports. Classically, GBS presents with hyporeflexia or areflexia, but preserved and brisk reflexes have been described in context with GBS variant, AMAN (acute motor axonal neuropathy), in approximately 33% of the cases. Preserved or exaggerated tendon reflexes with extensor plantar response is not usually seen in patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP). We report a rare case of AIDP with upper motor neuron signs in association with an antecedent hepatitis A infection.

Ophthalmoplegic migraine with trigeminal nerve involvement.

We report a 25-year-old man with a history of uncontrolled migrainous headaches who developed third nerve palsy and sensory loss over V1 distribution of trigeminal nerve, during an attack of severe migraine. Gadolinium-enhanced MRI of the brain and cavernous sinus was normal and did not disclose nerve enhancement. CT angiogram was also normal. The patient recovered uneventfully in 2 weeks on oral steroids. The commonest cranial nerve implicated in ophthalmoplegic migraine is the occulomotor nerve. Involvement of the fifth nerve has never been reported.

A rare case of alcoholic pellagra encephalopathy with startle myoclonus and marked response to niacin therapy: time for a new dictum?

We report a case of 56-year-old man, chronic alcoholic, presented to us with progressive weakness in all the four limbs with stiffness and gait disturbance since 1-year associated with cognitive impairment. On examination he had mild confusion, spastic quadriparesis with brisk reflexes, extensor plantars and cerebellar features. During the hospital stay myoclonus was noticed in the patient, which was startle in nature. He did not have dermatitis, ascites or any stigmata of liver failure. MRI of brain revealed bilateral subdural effusion, left focal subarachnoid haemorrhage at perisylvian area and diffuse cortical atrophy. He was treated with supportive measures including thiamine with which his condition worsened. His serum niacin was low. With a possibility of alcoholic pellagra encephalopathy (APE) the patient was treated with niacin. His clinical condition improved drastically over next 1 week and startle myoclonus disappeared, favouring the diagnosis of APE though multiple confounding factors were present.

Clinicodiagnostic features of tuberculous meningitis and the role of CSF PCR in early diagnosis: a study from north-west India.

The objective of this study was to study the clinical features and laboratory profile including acid fast bacillus microscopy, cerebrospinal fluid (CSF) culture and M. tuberculosis polymerase chain reaction (PCR) for an early diagnosis of tuberculous meningitis. Fifty consecutive patients, fulfilling the clinical criteria of tuberculous meningitis, were included in the study. All patients were subjected to detailed clinical and laboratory evaluation and radiological tests. CSF acid fast bacillus microscopy, culture and PCR were carried out in all and results were analysed. Majority of the patients presented with fever, headache, vomiting and signs of meningeal Irritation. Ziehl-Neelsen staining for acid-fast bacillus was positive in 4% cases, culture in 18% cases and CSF PCR for Mycobacterium tuberculosis was positive in 68%. Miliary pattern on chest x-ray was seen in 16% and CNS tuberculomas were seen in 14% cases. The CSF PCR estimation in clinically suspected cases of tuberculous meningitis may be an extremely valuable test for early diagnosis and institution of specific therapy.

Reversible neurological syndromes with atypical pneumonia.

Simultaneous or sequential involvement of lungs is frequently encountered with neurological syndromes like meningoencephalitis, cerebellitis, aseptic meningitis, transverse myelitis, or multiple cranial nerve palsies. However, pulmonary involvement is frequently overlooked when all the attention of physician is diverted to neurological disorder. Prompt and early recognition of such potentially treatable association is required to improve diagnostic and therapeutic outcome. We report six patients presenting with various neurological manifestations like meningitis, meningoencephalitis, and myelits associated with atypical pneumonia. With proper clinical correlation and relevant investigations, all of them were diagnosed in time and had remarkable recovery with appropriate treatment.

Subarachnoid hemorrhage with transient ischemic attack: another masquerader in cerebral venous thrombosis.

Cerebral venous thrombosis has a wide spectrum of clinical manifestations that may mimic many other neurological disorders and lead to frequent misdiagnoses or delay in diagnosis. The most frequent symptoms and signs are headache, seizures, focal deficits, and papilledema. A number of rare atypical manifestations have been described. Cerebral venous thrombosis may present with an isolated intracranial hypertension type picture, thunderclap headache, attacks of migraine with aura, isolated psychiatric disturbances, pulsatile tinnitus, isolated or multiple cranial nerve involvement, and occasionally as subarachnoid hemorrhage (SAH) or transient ischemic attack. Our patient presented with thunderclap headache and transient ischemic attack like episode with obvious SAH on CT scan. Acute SAH suggests the presence of a vascular lesion, such as ruptured aneurysm, and CVT is not generally considered in the diagnostic workup of SAH. The case emphasizes the importance of cerebral venous study in nonaneurysmal cases of SAH. It is important to have a high index of suspicion in such atypical cases to avoid delay in diagnosis.

The Global Mental Health Assessment Tool-validation in Hindi: A validity and feasibility study.

BACKGROUND: A computer-assisted interview, the Global Mental Health Assessment Tool-validation (GMHAT/PC) has been developed to assist general practitioners and other health professionals to make a quick, convenient, yet reasonably comprehensive standardized mental health assessment. GMHAT/PC has been translated into various languages including Hindi. This is the first study conducted in India, using the Hindi version GMHAT/PC of the series of studies assessing its validity in different cultures. AIM: The study aims to assess the feasibility of using a computer assisted diagnostic interview by health professionals and to examine the level of agreement between the Hindi version GMHAT/PC diagnosis and psychiatrists' ICD-10 based clinical diagnosis. DESIGN: Cross-sectional validation study. SETTING: Psychiatric clinic of a General Hospital and an out patient (Neurology) clinic in the Teaching General Hospital in Jaipur, India. MATERIALS AND METHODS: All consecutive patients attending the psychiatric out patient clinic were interviewed using GMHAT/PC and psychiatrists made a diagnosis applying ICD-10 criteria for a period of six weeks. A small sample of subjects was interviewed in a similar way in a Neurology clinic for four weeks. RESULTS: The mean duration of interview was under 17 minutes. Most patients were pleased that they were asked about every aspect of their mental health. The agreement between psychologists' GMHAT/PC interview diagnoses and psychiatrists' clinical diagnoses was excellent (Kappa 0.96, sensitivity 1.00, and specificity 0.94). CONCLUSION: GMHAT/PC Hindi version detected mental disorders accurately and it was feasible to use GMHAT/PC in Indian settings.